Cephalosporin intermediates

ABSTRACT

A cephalosporin derivative of the formula I: ##STR1## in which X is S, O, CH 2  or SO, ##STR2## represents one of C-7 acyl groups known in the cephalosporin art, R3 is hydrogen or methoxy, R4 is hydrogen, optionally substituted alkyl or allyl, and R5 is an aromatic heterocyclic ring system which is linked via carbon, and which contains a quaternized nitrogen atom.

This is a division of application Ser. No. 07/409,290, filed Sep. 19,1989, now U.S. Pat. No. 5,049,558, issued Sep. 17, 1991, which is acontinuation of application Ser. No. 06/738,646 filed May 28, 1985 nowabandoned.

This invention relates to cephalosporin derivatives which haveantibacterial activity.

According to the invention there is provided a cephalosporin derivativeof the formula I:

    [Formula I--given hereafter]

in which X is sulphur, oxygen, methylene or sulphinyl (R or Sconfiguration);

R1 is 2-aminothiazol-4-yl or 2-aminooxazol-4-yl each optionallysubstituted in the 5-position by fluorine, chlorine or bromine, or R1 is5-aminoisothiazol-3-yl, 5-amino-1,2,4-thiadiazol-3-yl,3-aminopyrazol-5-yl, 3-aminopyrazol-4-yl, 2-aminopyrimidin-5-yl,2-aminopyrid-6-yl, 4-aminopyrimidin-2-yl, 2-amino- 3,4-thiadiazol-5-ylor 5-amino-l-methyl-1,2,4-triazol-3-yl;

R50 is chloromethylene or a radical of the formula ═N.O.R2, wherein R2is hydrogen, (1-6C)alkyl, (3-8C)cyclo-alkyl,(1-3C)alkyl(3-6C)cycloalkyl, (3-6C)cycloalkyl(1-3C)alkyl, (3-6C)alkenyl,optionally substituted by carboxy, (5-8C)cycloalkenyl, (3-6C)alkynyl,(2-5C)alkylcarbamoyl, phenylcarbamoyl, benzylcarbamoyl,(1-4C)alkylcarbamoyl(1-4C)alkyl, di(1-4C)alkylcarbamoyl(1-4C)alkyl,(1-4C)haloalkylcarbamoyl(1-4C)alkyl, triphenylmethyl, (1-3C)haloalkyl,(2-6C)hydroxyalkyl, (1-4C)alkoxy(2-4C)alkyl, (1-4C)alkylthio(2-4C)alkyl,(1-4C)alkanesulphinyl(1-4C)alkyl, (1-4C)alkane-sulphonyl(1-4C)alkyl,(2-6C)aminoalkyl, (1-4C)alkyl-amino(1-6C)alkyl,(2-8C)dialkylamino(2-6C)alkyl, (1-5C)cyanoalkyl,3-amino-3-carboxypropyl, 2-(amidinothio)ethyl,2-(N-aminoamidinothio)ethyl, tetrahydropyran-2-yl, thietan-3-yl,2-oxopyrrolidinyl, or 2-oxotetrahydrofuran-3-yl,

or --R2 is the formula --(CH₂)_(n) --R6 in which n is 1 to 4 and R6 ispiperidino, pyrrolidino, morpholino, piperazino or N-methylpiperazino,each value of R6 being optionally substituted by (1-4C)alkyl, phenyl orbenzyl,

or --R2 is of the formula --(CH₂)_(m) --W--R7 in which m is 0 to 3, W issulphur or a direct bond, and R7 is phenyl or pyridinio(1-4C)alkylene orR7 is pyridyl, imidazolyl, 1,3,4-thiadiazolyl, tetrazolyl,1-(1-4C)alkyltetrazolyl, thiazolyl, isothiazolyl or isoxazolyl in whichthe link with W is via a carbon or uncharged nitrogen, each value of R7being optionally substituted, where possible, by one or two groupsselected from (1-4C)alkyl, amino, hydroxy, carboxy, carbamoyl, nitro,(2-5C)alkoxycarbonyl, cyano or sulpho,

or --R2 is of the formula --(CH₂)_(n) --CO--R8 in which n is 1 to 4 andR8 is (1-4C)alkyl, phenyl or benzyl,

or --R2 is of the formula --COR9 or --(CH₂)_(n) --OCO--R9 in which n is1-4 and R9is hydrogen, (1-4C)alkyl, (1-4C)haloalkyl, phenyl or benzyl,

or --R2 is of the formula --G--CH₂ --R10 in which G is carbonyl or adirect bond and R10 is phthalimido,

or --R2 is of the formula --NR11R12R13 in which R11, R12 and R13 are(1-4C)alkyl, or R11 is (1-4C)-alkyl and R12 and R13 are joined to form a(3-6C)carbocyclic ring, or R11, R12 and R13 are joined to form a1-azonia-4-azabicyclo[2,2,2]octane or1-azonia-3,5,7-triazatricyclo[3,3,1,1³,7 ]decane,

or --R2 is of the formula II

    [Formula II]

in which p is I or 2 and R14 and R15 are hydrogen or (1-4C)alkyl,

or --R2 is of the formula --P(O)R16R17 in which R16 is hydroxy,(1-4C)alkoxy, (2-8C)dialkylamino, phenoxy, phenylamino or one of thevalues given above for R6, and R17 is (1-4C)alkyl, (1-4C)alkoxy(2-8C)-dialkylamino, phenoxy, phenylamino, piperidino, pyrrolidino,morpholino, piperazino or N-methylpiperazino,

or --R2 is of the formula --CH₂ P(O)R18R19 in which R18 and R19 arehydroxy or (1-4C)alkoxy,

or --R2 is of the formula --CH(SR20)COOR21 in which R20 is (1-4C)alkyland R21 is hydrogen or (1-6C)alkyl,

or --R2 is of the formula III:

    [Formula III]

in which m is 0-3, R22 is hydrogen, (1-3C)alkyl or methylthio, R23 ishydrogen, (1-3C)alkyl, (C3-C7)cycloalkyl, cyano, carboxy,(2-5C)carboxyalkyl or methanesulphonylamino, or phenyl optionallysubstituted by amino or hydroxy, or R22 and R23 are joined to form,together with the carbon to which they are attached, a (3-7C)carbocyclic ring, and R24 is hydroxy, amino, (1-4C)alkoxy,(1-4C)alkylamino, phenylamino or of the formula R6 given above or of theformula NHOR25 in which R26 is hydrogen, (1-4C)alkyl, phenyl or benzyl,provided that when R2 contains phenyl, and unless otherwise stated, thephenyl is optionally substituted by 1 or 2 groups selected from halogen,hydroxy, amino, carboxy, nitro, carbamoyl, cyano and aminomethyl;

R3 is hydrogen or methoxy;

R4 is hydrogen, (1-4C)alkyl, halo(1-4C)alkyl, hydroxy(1-4C)alkyl,(1-4C)alkoxy(1-4C)alkyl, carboxy (1-4)alkyl, amino (1-4C)alkyl,cyano(1-4C)alkyl, (1-4C)alkanoylamino(1-4C)alkyl, allyl, furfuryl,benzyl or pyridyl(1-4C)alkyl;

R5 is an aromatic heterocyclic ring system which is linked via carbonand is one of the formula IV to LI inclusive each of these ring systemsbeing optionally substituted where possible, on a carbon atom or atoms,by one, two or three substituents selected from halogen, (1-6C)alkyl,carboxy, (2-6C)alkoxycarbonyl, (2-6C)- alkoxycarbonyl(1-4C)alkyl,(1-6C)alkoxy, (1-6C)alkylthio, cyano, (2-4C)cyanoalkyl, amino,(1-6C)alkylamino, (2 8C)dialkylamino, benzylamino (optionallysubstituted in the benzene ring thereof by nitro), thenylamino,allylamino, (1-6C)aminoalkylamino, (1-6C)alkoxy(1-6C)alkylamino,(1-6C)hydroxyalkylamino, hydroxy, mercapto, carbamoyl,(2-6C)alkylcarbamoyl, (3-10C)dialkylcarbamoyl, phenylthio andheteroarylthio wherein heteroaryl is a 5- or 6-membered ring containing1, 2 or 3 hetero atoms selected from oxygen, nitrogen and sulphur;

and in which Y is oxygen, sulphur or NR27;

Z is nitrogen or CH;

one of A, B, D and E is +NR27 and the remainder are nitrogen;

and ring systems of Formula IV, XVI or XVII, which are optionally fused,on a carbon-carbon bond, with a 5- to 7-membered saturated carbocyclicring;

R27 is nitrogen-linked and is (1-6C)alkyl, (1-6C)alkyl(2-6C)alkenyl,(2-6C)alkenyl, (2-8C)alkoxyalkyl, carboxy(1-6C)alkyl,[(1-6C)alkoxy]carbonyl(1-6C)alkyl, carbamoyl(1-6C)alkyl,carboxyamino-carbonyl(1-6C)alkyl,[(1-6C)alkoxy]carbonylamino-carbonyl(1-6C)alkyl, [(2-8C)alkanoyl]methyl,benzoylmethyl, (1-6C)hydroxyalkyl, (1-6C)alkylamino, orphenyl(1-6C)alkyl or phenyl, each optionally substituted by 1 or 2groups selected from halogen, hydroxy, amino, carboxy, nitro, carbamoyl,cyano, trifluoromethyl, and aminomethyl;

R26 is hydrogen, (1-6C)alkyl, phenyl or benzyl;

R28 is cyano(3-6C)cycloalkenyl, or phenyl optionally substituted by 1 or2 groups selected from halogen, nitro, amino, (1-4C)alkanoyl,(1-4C)alkanoylamino, halo(1-4C)alkyl, hydroxy, carboxy,(2-6C)alkoxycarbonyl, carbamoyl, mono- or di(1-4C)alkylcarbamoyl, cyano,mesyl, vinyl, and sulpho; or R28 is (2-6C)alkenyl, optionallysubstituted by halogen, cyano, carbamoyl, mono- or di(1-4Calkyl)carbamoyl, piperidinocarbonyl or morpholinocarbonyl,cyano(1-4C)alkyl, 2-ureidoethyl, 2-thioureidoethyl,2-(thioacetyl-amino)ethyl, sulphamoyl, 2-amino-2-carboxyethyl,acetylaminomethyl, phthalimidomethyl, 4,5-dihydroimidazo1-2-ylmethyl,3,4,5,6-tetrahydro-pyrimidin-2-ylmethyl,2-(1,2,3,6-tetrahydro-2,6-dioxopurin-7-yl)ethyl, 2-hydroxyiminopropyl(syn or anti) or 2-[(1-4C)alkoxyimino]propyl (syn or anti),

or --R28 is of the formula --(CH₂)₂ --NR29R30R31 in which R29, R30 andR31 are (1-4C)alkyl, or --R28 is of the formula --(CH₂)_(q) --R32 inwhich q is 0-2 and --R32 is pyridine, pyridazine, pyrimidine, pyrazine,1,2,5,6-dihydro-5,6-dioxo-1,2,4-triazine,2-[(1-4C)alkyl]-1,2,5,6-dihydro-5,6-dioxo-1,2,4-triazine,1-[(1-4C)alkyl]tetrazole, furan, thiophene, pyrrole,1-[(1-4C)alkyl]pyrrole, oxazole, thiazole, imidazole,1-[(1-4C)alkyl]imidazole, isoxazole, isothiazole, pyrazole,1,2,3-thiadiazole, 1-[(1-4C)alkyl]pyrazole, benzfuran, benzthiophene,indole, oxindole, 1-[(1-4C)alkyl]indole, benzoxazole, benzthiazole,benzimidazole, 1-[(1-4C)alkyl]benzimidazole,3,4-dihydro-4-oxo-2H-benzo[e]oxazine each of these ring systems beinglinked to (CH₂)_(q) through carbon and each ring system being optionallysubstituted by halogen, amino, (1-6C)alkyl, (1-4C)-haloalkyl,(3-6C)cycloalkyl, (2-6C)alkenyl, carboxy, (2-6C)alkoxycarbonyl,(1-6C)alkoxy, cyano, (2-6C)cyanoalkenyl, carbamoyl, mono- or di(1-4C)alkylcarbamoyl, (1-4C)alkanoylamino, guanidino, hydroxy, nitro,amino; and for those ring systems which contain nitrogen, the N-oxidesthereof where chemically possible;

or, when R4 is hydrogen then R5 is also a radical of the formula LI:

    [Formula LI]

in which R28 is 2-guanidino-thiazol-4-ylmethyl, hydroxybenzoyl-methyl,2-thenyl, 2-imidazolylmethyl or cinnamyl, optionally substituted byhalogen, (1-6C)alkyl, hydroxy, (1-4C)alkoxy, carboxy,(2-6C)alkoxycarbonyl, nitro or carbamoyl,

and when R4 is other than hydrogen then R5 is also a radical of theformula LII in which ring J is pyridine, pyrimidine, oxazole, thiazole,isoxazole, isothiazole or imidazole to each of which is optionallyfused, when possible, a benzene, cyclopentane or cyclohexane ring;

R33 is hydrogen, amino, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)alkenyl,(2-8C)alkoxyalkyl, --(CH₂)_(t) --COOR35, --(CH₂)_(t) --CONH₂,--(CH₂)_(t) --NHCO--R36 or --(CH₂)_(t) S(O)_(s) --R36 in which t is 1-6,R35 is hydrogen or (1-6C)alkyl, s is 0, 1 or 2, and R36 is (1-6C)alkylor (1-6C)alkoxy,

or R33 is (3-8C)alkanoylmethyl, benzoylmethyl,(1-6C)primaryhydroxyalkyl, (1-6C)primaryaminoalkyl,(1-4C)alkylamino(1-6C)alkyl, di(1-4C)alkylamino(1-6C)alkyl,carbamoyl(1-4C)alkyl, mono- or di(1-4C)alkylcarbamoyl(1-4C)alkyl,(1-4C)alkoxy(1-4C)alkyl, (1-6C)alkoxy, (1-4C)alkoxy(2-4C)alkoxy(1-4C)alkyl, (1-6C)alkylamino, phenyl(1-6C)alkyl orphenyl(1-6C)alkoxy or of the formula (CH₂)₂ N═CR37NR38R39 or (CH₂)_(n)C(NR37)NR38R39 or a tautomer thereof in which R37, R38 and R39 arehydrogen or (1-4C)alkyl;

R34 is hydrogen or one or two substituents selected from halogen, amino,nitro, (1-6C)alkyl, carboxy, (2-6C)alkoxycarbcnyl, (1-6C)alkoxy, cyano,carbamoyl, (1-6C)haloalkyl, (1-6C)azidoalkyl, (1-6C)aminoalkyl,(2-4C)aminoalkylthio(1-4C)alkyl, (2-6C)alkanoylamino,(2-4C)alkanoylamino(1-4C)alkyl, (2-6C)alkanoyloxy(1-4C)alkyl, benzyl,benzyloxy and heteroarylthio,

wherein, when R33 contains phenyl, the phenyl is optionally substitutedby halogen, nitro, (1-6C)alkyl, hydroxy, (1-4C)alkoxy, carboxy,(2-6C)alkoxycarbonyl, carbamoyl, sulphamoyl, sulpho, mono- ordi(1-4C)alkylcarbamoyl, or mono- or di-(1-4C)alkylsulphamoyl, andwherein when R34 is heteroarylthio, the heteroaryl ring is a 5- or6-membered ring containing 1,2 or 3 hetero atoms selected from oxygen,nitrogen and sulphur;

and the salts formed with acids and bases which afford pharmaceuticallyacceptable anions and cations respectively.

It is to be understood that in the above formula I and throughout thisspecification, the illustrated stereochemistry of the ceph-3-em nucleus,and its optional modifications at the 1-position, is the absoluteconfiguration. It is also to be understood that, since R5 contains aquaternary nitrogen, the compounds of the formula I will normally existin zwitter-ionic form, involving the quaternary nitrogen and the carboxygroup. When the compound of the formula I contains further acidic orbasic substituents, it is to be understood that the possibility of adouble zwitter-ionic form of the compound will arise. Alternatively,exogenous anions or cations may be included, to formpharmaceutically-acceptable base-addition or acid-addition salts, asdefined above.

A particular value for R2 is hydrogen, methyl, ethyl, isopropyl,t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,methylcyclopropyl, methylcyclobutyl, methylcyclopentyl,methylcyclohexyl, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, allyl, cyclopentenyl, cyclohexenyl, propargyl,methylcarbamoyl, ethylcarbamoyl, phenylcarbamoyl, benzylcarbamoyl,triphenylmethyl, 2-chloroethyl, 2-fluoroethyl, 2-bromoethyl,2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 2-ethoxyethyl,2-methylthioethyl, 2-methanesulphinylethyl, 2-methanesulphonylethyl,2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 2-dimethylaminoethyl,cyanomethyl, 2-cyanoethyl, azidomethyl, 2-azidoethyl, ureidomethyl,3-amino-3-carboxypropyl, 2-(amidino)ethyl, 2-(N-aminoamidino)ethyl,tetrahydropyran-2-yl, thietan-3-yl or 2-oxo-tetrahydrofuran-3-yl,

or, when R2 is of the formula --(CH₂)_(n) --R6 in which n is 1 to 4 andR6 is piperidino, pyrrolidino, morpholino, piperazino orN-methylpiperazino, a particular value of R2 is when each value of R6 isoptionally substituted by methyl, phenyl or benzyl,

or, when R2 is of the formula --(CH₂)_(m) --W--R7 in which m is 0 to 3,W is sulphur or a direct bond, particular values for R2 are when R7 isphenyl, pyridiniomethylene, 2-pyridinioethylene or R7 is pyridyl,imidazolyl, 1,3,4-thiadiazolyl, tetrazolyl, 1-methyltetrazolyl,thiazolyl, isothiazolyl or isoxazolyl in which the link with W is via acarbon or uncharged nitrogen, each value of R7 being optionallysubstituted, where possible, by one or two groups selected from methyl,amino, hydroxy, carboxy, carbamoyl, nitro, methoxycarbonyl,ethoxycarbonyl, cyano or sulpho,

or, when R2 is of the formula --(CH₂)_(n) --CO--R8 in which n is 1 to 4,a particular value for R2 is when R8 is methyl, ethyl, phenyl or benzyl,

or, when R2 is of the formula --COR9 or --(CH₂)_(n) --OCO--R9 in which nis 1-4, a particular value for R2 is when R9 is hydrogen, methyl,chloromethyl, bromomethyl, 2-chloroethyl, 2-bromoethyl, phenyl orbenzyl,

or, when R2 is of the formula --G--CH₂ --R10, a particular value for R2is when G is carbonyl or a direct bond and RIO is phthalimido,

or, when R2 is of the formula --NR11R12R13, a particular value for R2 iswhen R11, R12 and R13 are methyl or ethyl, or R11 is methyl or ethyl andR12 and R13 are joined to form a cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl ring, or R11, R12 and R13 are joined to form a1-azonia-4-azabicyclo[2,2,2]octane or1-azonia-3,5,7-triazatricyclo[3,3,1,1³,7 ]decane,

or, when R2 is of the formula II:

    [Formula II]

in which p is 1 or 2, a particular value for R2 is when and R14 and R15are hydrogen or methyl,

or when R2 is of the formula --P(O)R16R17, a particular value for R2 iswhen R16 is hydroxy, methoxy, ethoxy, dimethylamino, diethylamino,phenoxy, phenylamino, or one of the particular values given above forR6, and R17 is methyl, ethyl, methoxy, ethoxy, dimethylamino,diethylamino, phenoxy, phenylamino, piperidino, pyrrolidino, morpholino,piperazino or N-methylpiperazino,

or, when R2 is of the formula --CH₂ P(O)R18R19, a particular value forR2 is when R18 and R19 are hydroxy, methoxy or ethoxy,

or, when R2 is of the formula --CH(SR20)COOR21, a particular value forR2 is when R20 is methyl or ethyl and R21 is hydrogen, methyl, ethyl orisopropyl,

or, when R2 is of the formula III:

    [Formula III]

in which m is 0-3, a particular value for R2, when m=0, is when R22 ishydrogen, methyl or methylthio, R23 is hydrogen, methyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyano, carboxy, carboxymethyl,2-carboxyethyl or methanesulphonylamino, or phenyl optionallysubstituted by amino or hydroxy, or R23 and R24 are joined to form,together with the carbon to which they are attached, a cyclopropane,cyclobutane, cyclopentane, cyclohexane or cycloheptane ring and R25 ishydroxy, amino, methoxy, ethoxy, methylamino, ethylamino, phenylamino orone of the particular values for R6 given above or of the formula NHOR25in which R25 is hydrogen, methyl, ethyl, phenyl or benzyl,

provided that when R2 contains phenyl, and unless otherwise statedabove, the phenyl is optionally substituted by 1 or 2 groups selectedfrom fluorine, chlorine, bromine, hydroxy, amino, carboxy, nitro,carbamoyl, cyano and aminomethyl.

A particular value for R3 is hydrogen or methoxy.

A particular value for R4 is hydrogen, methyl, ethyl, n-propyl,isopropyl, 2-fluoroethyl, 2-chloroethyl, 2-hydroxymethyl,2-methoxyethyl, carboxymethyl, (R) and (S)-1-carboxyethyl, 2-aminoethyl,2-cyanoethyl, 2-formamidoethyl, allyl, furfuryl, benzyl or4-pyridylmethyl.

A particular value for an optional substituent on one of the ringsystems of the formula IV to LI inclusive is one, two or threesubstituents selected from fluorine, chlorine, bromine, methyl, ethyl,n-propyl, isopropyl, carboxy, methoxycarbonyl, ethoxycarbonyl,methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxy, ethoxy,methylthio, ethylthio, cyano, cyanomethyl, 2-cyanoethyl, amino,methylamino, ethylamino, isopropylamino, dimethylamino, benzylamino,(optionally substituted in the benzene ring by nitro), allylamino,2-aminoethyl-amino, 2-methoxyethylamino, 2-hydroxyethylamino, hydroxy,mercapto, carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl,phenylthio and heteroarylthio in which the heteroaryl ring is a furan,thiophene, imidazole, thiazole, pyrazole, thiadiazole, pyridine,pyrimidine, pyrazine or pyridazine.

A particular value for R27 is methyl, ethyl, n-propyl, isopropyl, allyl,methoxymethyl, 2-methoxyethyl, carboxymethyl, 2-carboxyethyl,methoxycarbonylmethyl, 2-methoxycarbonylethyl, carbamoylmethyl,2-carbamoylethyl, carboxyaminocarbonylmethyl,2-(carboxyaminocarbonyl)ethyl, methoxycarbonylaminocarbonylmethyl,2-(methoxycarbonylaminocarbonyl)ethyl, acetylmethyl, propionylmethyl,benzoylmethyl, hydroxymethyl, 2-hydroxyethyl, methylamino, ethylamino,benzyl or 2-phenethyl, or phenyl optionally substituted by 1 or 2 groupsselected from fluorine, chlorine, bromine, hydroxy, amino, carboxy,nitro, carbamoyl, cyano, trifluoromethyl and aminomethyl.

A particular value for R26 is hydrogen, methyl, ethyl, n-propyl,isopropyl, phenyl or benzyl.

A particular value for R28 is 3-cyanocyclopent-2-enyl or phenyloptionally substituted by 1 or 2 groups selected from fluorine,chlorine, bromine, nitro, amino, acetyl, acetamido, trifluoromethyl,hydroxy, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl,methylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, cyano, mesyl andsulpho,

or vinyl, 2,4-pentadienyl, 3-chloroallyl (cis and trans), 3-cyanoallyl,cyanomethyl, 3-cyanopropyl, 2-ureidoethyl, 2-thioureidoethyl,2-(thioacetylamino)ethyl, sulphamoyl, 2-amino-2-carboxyethyl,acetylaminomethyl, phthalimidomethyl, 4,5-dihydroimidazol-2-ylmethyl,3,4,5,6-tetrahydropyrimidin-2-ylmethyl,2-(1,2,3,6-tetrahydro-2,6-dioxopurin-7-yl)ethyl, 2-hydroxyiminopropyl(syn or anti), 2-(mathoxyimino)propyl (syn or anti) or2-(ethoxyimino)propyl (syn or anti),

or of the formula --(CH₂)₂ --NR29R30R31 in which R29, R30 and R31 aremethyl or ethyl,

or of the formula --(CH₂)_(q) --R32 in which q is 0-2 and R32 ispyridine, pyridazine, pyrimidine, pyrazine,1,2,5,6-dihydro-5,6-dioxo-1,2,4-triazine, 2-(methyl orethyl)-1,2,5,6-dihydro-5,6-dioxo-1,2,4-triazine, 1-(methyl orethyl)tetrazole, furan, thiophene, pyrrole, 1-(methyl or ethyl)pyrrole,oxazole, thiazole, imidazole, 1-(methyl or ethyl)imidazole, isoxazole,isothiazole, pyrazole, 1-(methyl or ethyl) pyrazole, 1,2,3-thiadiazole,benzfuran, benzthiophene, indole, 1-(methyl or ethyl)indole,benzoxazole, benzthiazole, benzimidazole,3,4-dihydro-4-oxo-2H-benzo[eloxazine, 1-(methyl or ethyl)benzimidazole,each of these ring systems being linked to (CH₂)_(q) through carbon andeach ring system being optionally substituted by fluorine, chlorine,bromine, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl,cyclopropylmethyl, formamido, carboxy, methoxycarbonyl, ethoxycarbonyl,methoxy, ethoxy, cyano, 3-cyanoallyl, carbamoyl, methylcarbamoyl,dimethylcarbamoyl, hydroxy, guanidino, nitro, amino and for those ringsystems which contain nitrogen, the N-oxides thereof where chemicallypossible;

or, when R4 is hydrogen --R28 is 2-guanidinothiazol-4-ylmethyl,3-hydroxybenzoylmethyl, 2-thenyl, 2-imidazolylmethyl or cinnamyl,optionally substituted by fluorine, chlorine, bromine, methyl, ethyl,n-propyl, isopropyl, hydroxy, methoxy, ethoxy, carboxy, methoxycarbonyl,ethoxycarbonyl or carbamoyl;

and when R4 is other than hydrogen, a further particular value for R5 isof the formula LI:

    [Formula LII]

in which ring J is pyridine, pyrimidine, oxazole, thiazole, isoxazole,isothiazole or imidazole to each of which is optionally fused, whenpossible, a benzene, cyclopentane or cyclohexane ring.

A particular value for R33 is hydrogen, amino, methyl, ethyl, n-propyl,isopropyl, t-butyl, cyclopropyl, cyclobutyl, allyl, 3-chloroallyl (cisor trans) methoxymethyl, --(CH₂)_(t) --COOR35, (CH₂)_(t) --CONH₂,(CH₂)_(t) --NH--CO--R36 or --(CH₂)_(t) S(O)_(s) --R36 in which t is 1-6,R35 is hydrogen, methyl or ethyl, s is 0, 1 or 2 and R36 is methyl,ethyl, methoxy or ethoxy,

or acetylmethyl,propionylmethyl, benzoylmethyl, hydroxymethyl,2-hydroxyethyl, aminomethyl, 2-aminoethyl, 2-methylaminoethyl,2-dimethylaminoethyl, carbamoylmethyl, methylcarbamoylmethyl,dimethylcarbamoylmethyl, 2-methoxymethyl, methoxy, ethoxy,2-methoxyethoxymethyl, methylamino, ethylamino, benzyl, 2-phenethyl,2-(3,4-dihydro-4-oxo-H-benzo[e]- oxazin-2-yl)ethyl, benzyloxy or2-phenylethoxy or of the formula (CH₂)₂ --N═CR37NR38R39 or (CH₂)₂C(N37)NR38R39 in which R37, R33 and R39 are hydrogen or methyl, whereinwhen R33 contains phenyl the phenyl is optionally subtituted byfluorine, chlorine, bromine, methyl, ethyl, hydroxy, methoxy, ethoxy,carboxy, methoxycarbonyl, ethoxycarbonyl, sulpho, carbamoyl,methylcarbamoyl or dimethylcarbamoyl.

A particular value for R34 is hydrogen or one or two substituentsselected from fluorine, chlorine, bromine, amino, nitro, methyl, ethyl,carboxy, methoxycarbonyl, ethoxycarbonyl, methoxy, ethoxy, cyano,carbamoyl, chloromethyl, 2-chloroethyl, azidomethyl, aminomethyl,2-aminoethyl, 2-aminoethylthiomethyl, acetylamino, propionylamino,acetylaminomethyl, acetoxymethyl, benzyl, benzyloxy, 2-thenylamino orheteroarylthio and in which when R34 is heteroarylthio the heteroarylring is furan, thiophene, pyrrole, imidazole, thiazole, isothiazole,oxazole, isoxazole, pyrazole, thiadiazole, pyridine,

A particular acid which affords a pharmaceutically-acceptable anion is,for example, hydrochloric, hydrobromic, phosphoric, sulphuric, citric ormaleic acid.

A particular base which affords a pharmaceutically acceptable cation is,for example, a base containing an alkali metal, (e.g. sodium orpotassium) or an alkaline earth metal (e.g. calcium or magnesium), or aprimary, secondary or tertiary organic amine (e.g. triethylamine,morpholine, N-methylpiperidine, N-ethylpiperidine, procaine,dibenzylamine or N,N'-dibenzylethylenediamine), or other amine which hasbeen used to form salts with cephalosporins.

The following are preferred features of the cephalosporin derivative ofthe invention. When any one of these features is taken, either singly orin combination, with the other general or particular features of thecephalosporin derivative of the invention listed above, there areobtained preferred sub-groups of compounds.

1. X is sulphur.

2. R1 is 2-aminothiazol-4-yl or 5-amino-1,2,4-thiadiazol-3-yl.

3. R50 is chloromethylene.

4. R50 is ═N.OR2 in which R2 is (1-6C)alkyl, (3-6)alkenyl optionallysubstituted by carboxy, (3-6C)alkynyl, (3-8C)cycloalkyl,(3-6C)cycloalkyl(1-3C)alkyl, (1-4C)haloalkyl, (1-5C)cyanoalkyl,(2-6C)hydroxyalkyl, (1-4C)alkoxy(2-4C)alkyl, (2-6C)aminoalkyl or benzyl.

5. R2 is methyl, ethyl, i-propyl, allyl, propargyl, cyclopentyl,cyclopropylmethyl, 2-chloroethyl, 2-fluoroethyl, 2-bromoethyl,cyanomethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-ethoxyethyl or benzyl.

6. R2 is of the formula III.

7. In formula III, m is 0.

8. In formula III, R24 is hydroxy or (1-4C)alkoxy.

9. In formula III, R22 and R23 are both hydrogen or (1-3C)alkyl, or R22and R23 are joined to form, together with the carbon to which they areattached, a (3-7C) carbocyclic ring.

10. In formula III, R22 and R23 are both hydrogen or methyl, or R22 andR23 are joined to form, together with the carbon to which they areattached, a cyclobutane or cyclopentane ring.

11. R5 is of the formula XVI, XXVIII, XLII, XLIII, XLVI, XLVII or LI,each of these ring systems being optionally substituted, where possible,on a carbon atom or atoms, by one or two substituents selected fromhalogen, (1-6C)alkyl, carboxy, (2-6C)alkoxycarbonyl(1-4C)alkyl,(1-6C)alkoxy, (1-6C)alkylthio, amino, (1-6C)alkylamino,(2-8C)dialkylamino, benzylamino, optionally substituted in the benzenering thereof by nitro, allylamino, (1-6C)aminoalkylamino, (1-6C)-alkoxy(1-6C)alkylamino, (1-6C)hydroxyalkylamino and hydroxy.

12. In formulae XVI, XXVIII, XLII, XLIII, XLVI and XLVII, the ringsubstituents are selected from chlorine, fluorine, methyl, ethyl,n-propyl, isopropyl, carboxy, methoxycarbonylmethyl,ethoxycarbonylmethyl, methoxy, ethoxy, methylthio, amino,isopropylamino, dimethylamino, p-nitrobenzylamino, allyamino,2-aminoethylamino, 2-methoxyethylamino, 2-hydroxyethylamino and hydroxy.

13. In formulae XVI, XXVIII and XLVII, R27 is (1-6C)alkyl, allyl orphenyl optionally substituted by nitro or trifluoromethyl.

14. In formulae XLII and LI, R28 is phenyl optionally substituted by 1or 2 groups selected from halogen, nitro, amino, (1-4C)alkanoyl,(1-4C)alkanoylamino, (1-4C)haloalkyl, hydroxy, (2-6C)alkoxycarbonyl,carbamoyl, mono- or di(1-4C)alkylcarbamoyl, cyano, mesyl and vinyl.

15. In formulae XLII and LI, the substituents in R28, when R28 isphenyl, are selected from chlorine, fluorine, nitro, amino, acetyl,acetamido, trifloromethyl, hydroxy, methoxycarbonyl, ethoxycarbonyl,carbamoyl, methylcarbamoyl, dimethylcarbamoyl, cyano, mesyl and vinyl.

16. In formulae XLII and LI, R28 is (2-6C)alkenyl, optionallysubstituted by halogen or cyano, cyano(1-4C)alkyl, phthalimidomethyl or2-(1,2,3,6-tetrahydro-2,6-dioxopurin-7-yl)ethyl.

17. In formulae XLII and LI, R28 is vinyl, 2,4-pentadienyl,3-cyanopropyl, 3-chloroallyl, 3-cyanoallyl, phthalimidomethyl or2-(1,2,3,6-tetrahydro-2,6-dioxopurin-7-yl)ethyl.

18. In formulae XLII and LI, R28 is of the formula (CH₂)_(q) --R32,wherein q is 0 or 1 and R32 is pyridine, pyridine-N-oxide, pyridazine,pyrazine, pyrazine-N-oxide, pyrimidine, furan, thiophene, thiazole,imidazole, 1,2,3-thiadiazole, oxazole, oxindole, benzimidazole or3,4-dihydro-4-oxo-2H-benzo[e]-oxazine, optionally substituted byhalogen, amino, (1-6C)alkyl, (1-4C)haloalkyl, (3-6C)cycloalkyl,(2-6C)alkoxycarbonyl, cyano, (2-6C)cyanoalkenyl, carbamoyl, mono- ordi(1-4C)alkylcarbamoyl, (1-4C)alkanoylamino, guanidino, hydroxy, nitroor amino.

19. The substituent in R32 is chlorine, fluorine, amino, methyl, ethyl,n-propyl, isopropyl, trifluoromethyl, cyclopropyl, methoxycarbonyl,ethoxycarbonyl, cyano, 3-cyanoallyl, carbamoyl, methylcarbamoyl,dimethylcarbamoyl, formamido, guanidino, hydroxy, nitro or amino.

20. In formula LII, R33 is (1-6C)alkyl and R34 is hydrogen.

21. R33 is methyl or ethyl.

22. R4 is hydrogen, (1-4C)alkyl, halo(1-4C)alkyl, hydroxy(1-4C)alkyl,(1-4C)alkoxy(1-4C)alkyl, carboxy(1-4C)alkyl, amino(1-4C)alkyl,cyano(1-4C)alkyl, (1-4C)alkanoylamino(1-4C)alkyl, allyl, furfuryl,benzyl or pyridyl (1-4C)alkyl.

23. R4 is hydrogen, methyl, ethyl, 2-fluoroethyl, 2-chloroethyl,2-hydroxyethyl, 2-methoxyethyl, carboxymethyl, 2-aminoethyl,2-cyanoethyl, 2-formamidoethyl, allyl, furfuryl, benzyl or4-pyridylmethyl.

24. R5 is of the formula XVI, XXVIII, XLII, XLIII, XLVI, LI or LII.

25. R5 is of the formula XVI wherein the ring is substituted by(1-6C)alkyl and/or amino.

26. R5 is of the formula XXVIII wherein Y is sulphur, Z is CH and R27 is(1-6C)alkyl, particularly methyl.

27. R5 is of the formula XLII wherein R29 is (2-6C)alkenyl, optionallysubstituted by cyano or halogen, particularly chlorine, or R28 is(CH₂)_(q) R32 in which q is 1 and R32 is 1,2,3-thiadiazole, thiophen orthiazole optionally substituted by guanidino or cyano.

28. R5 is of the formula XLIII wherein Y is sulphur.

29. R5 is of the formula XLVI wherein the optional bond is a doublebond.

30. R5 of the formula LI wherein R28 is (CH₂)_(q) R32 in which q is 1and R32 is thiophen.

31. R5 is of the formula LII wherein ring J is pyridine, R33 is amino,(1-6C)alkyl, (1-6C)primary-aminoalkyl, or benzyl optionally substitutedby nitro, and R34 is hydrogen or (1-6c)alkyl.

Particular compounds of the invention are described in the Examples, andof these, the group consisting compounds of Examples 37, 55, 60, 64, 66,71, 81, 87, 88, 95, 96, 104, 110, 111, 149, 150, 151, 153, 177, 178,184, 185, 188, 195, 202, 209, 213, 215, 218, 219, 225, 226, 232, 244,249, 251, 255, and 261 is preferred. A more preferred group consists ofthe compounds of Examples 37, 55, 60, 64, 66, 71, 88, 96, 104, 110, 149,150, 153, 178, 184, 213, 219, 225, 244, 249, 255, and 261. Within thisgroup, the compounds of Examples 60, 66, 104, 110, 184, 188, 219, 225,255 and 261 are particularly preferred, and of these the compounds ofExamples 110, 184, 219 and 225 are especially preferred.

The cephalosporin derivatives of the formula I may be manufactured bymethods known in themselves for the manufacture of chemically analogouscompounds. The for following processes, R1, R2, R3, R4, R5, R50 and Xhaving the meanings stated above, unless indicated otherwise, andtherefore provided as further features of the invention.

The process of the invention is characterised by

(a) reaction of a compound of the formula LIII

    [Formula LIII]

with a compound of the formula R5-R40 in which R40 is a displaceableradical [e.g. fluorine, chlorine, bromine, (1-6C)alkoxy,(1-6C)alkylthio, (1-6C)alkanesulphinyl or (1-6C)alkanesulphonyl].

(b) reaction of a compound of the formula LIV:

    [Formula LIV]

with an acid of the formula LV:

    [Formula LV]

or an activated derivative thereof.

(c) deprotection, to form carboxy, of the corresponding compound whichcarries a protecting group in place of the acidic hydrogen atom of thecarboxy

(d) deprotection, to form a primary or secondary amino, of thecorresponding compound which carries a protecting group in place of theamino hydrogen.

(e) for those compounds in which X is sulphinyl, oxidation of thecorresponding compound in which X is sulphur.

(f) reaction of a compound of the formula LVI

    [Formula LVI]

with a compound of the formula R2--O--NH₂.

(g) for those compounds in which R2 is other than hydrogen, reaction ofa compound of the formula I in which R2 is hydrogen with a compound ofthe formula R41-R40 in which R40 is a displaceable radical and R41 isone of the values given above for R2, other than hydrogen.

(h) for those compounds which contain an aminophenyl group, thereduction of the corresponding nitrophenyl compound.

(i) the reaction of a compound of the formula LVIII, wherein R40 is adisplaceable radical, with a compound of the formula R4R5NH.

When the process of the invention manufacture the compound of theformula I in the form of the zwitterion, and a salt is required, thecompound of the formula I in the zwitterionic form is reacted with anacid which affords a pharmaceutically-acceptable anion, or with a basewhich affords a pharmaceutically-acceptable cation.

The starting material of the formula LIII may be prepared by acylationof the appropriate 7-amino-3-azidomethylcephalosporin derivative with anacid of the formula LV, or an activated derivative thereof, followed byreduction of the 3-azidomethyl group to the 3-aminomethyl group. Duringthis process it may be necessary to protect amino and carboxy groups.There is thus obtained the compound of the formula LIII in which R4 ishydrogen. This procedure is illustrated in Examples 1-4, 5-6, 7-14 and15-16. When R4 is other than hydrogen, the compound in which R4 ishydrogen is then alkylated or benzylated.

The starting material of the formula LIV may be prepared by reaction ofthe compound of the formula LVII:

    [Formula LVII]

with a compound of the formula R5-R40 in which R40 is a displaceableradical. During this reaction it may be necessary to protect the 7-aminoand/or 3-carboxy group.

The starting material of the formula LIV in particularly valuable and isregarded as a further feature of the invention.

The starting materials of the formulae LV, LVI, LVII and LVIII areprepared by conventional methods known in the chemical literature foranalogous compounds.

As noted above the cephalosporin derivatives of the invention haveantibacterial properties. Thus they are useful antibacterial agents,many of them having a broad spectrum of activity in vitro againststandard laboratory microorganisms, both Gram-negative and Gram-positive, which are used to screen for activity against pathogenicbacteria. The antibacterial spectrum and potency of a particularcompound may be determined in a standard test system.

The antibacterial properties of the compounds of the invention may alsobe demonstrated in conventional mouse protection tests, and thepreferred compounds of this invention have MIC₅₀ values of less than 2μg./ml. against both Pseudomonas aeruginosa and Staphyllococcus aureus.

Cephalosporin derivatives have generally been found to be relativelynon-toxic to warm-blooded animals, and this generalisation holds truefor the compounds of the present invention. A number of compounds wereadministered to mice at doses in excess of those required to affordprotection against bacterial infections, and no overt toxic symptoms orside effects attributable to the administered compounds were noted.

According to a further feature of the invention there is provided apharmaceutical composition which comprises a cephalosporin derivative ofthe invention in association with a pharmaceutically-acceptable diluentor carrier.

The pharmaceutical composition of the invention may, for example, be ina form suitable for oral, rectal or parenteral administration, for whichpurposes it may be formulated by means known to the art into the formof, for example, tablets, capsules, aqueous or oily solutions orsuspensions, emulsions, dispersible powders, suppositories and sterileinjectable aqueous or oily solutions or suspensions.

In addition to the cephalosporin derivative of the formula I thepharmaceutical composition of the invention may also contain, or beco-administered with, one or more known drugs selected from otherclinically useful antibacterial agents (for example other beta-lactamsor aminoglycosides), inhibitors of beta-lactamase (for exampleclavulanic acid), renal tubular blocking agents (e.g. probenicid) andinhibitors of metabolising enzymes (for example inhibitors ofpeptidases, for example Z-2-acylamino-3-substituted propenoates).

A preferred pharmaceutical composition of the invention is one suitablefor intravenous, subcutaneous or intramuscular injection, for example asterile injectable containing between 1 and 10% w/w of the cephalosporinderivative, or one suitable for oral administration in unit dosage form,for example a tablet or capsule which contains between 100 mg. and 1 g.of the cephalosporin derivative.

The pharmaceutical composition of the invention will normally beadministered to man in order to combat infections caused by bacteria, inthe same general manner as that employed for cephalothin, cefoxitin,cephradine and other known clinically used cephalosporin derivatives,due allowance being made in terms of dose levels for the potency of thecephalosporin derivative of the present invention relative to the knownclinically used cephalosporins. Thus each patient will receive a dailyintravenous, subcutaneous or intramuscular dose of 0.5 to 50 g., andpreferably 0.5 to 10 g., of the cephalosporin derivative, thecomposition being administered 1 to 4 times per day. The intravenous,subcutaneous and intramuscular dose will be given by means of a bolusinjection. Alternatively the intravenous dose may be given by continuousinfusion over a period of time. Alternatively each patient will receivea daily oral dose which is approximately equivalent to the dailyparenteral dose. Thus a preferred daily oral dose is 0.5 to 10 g. of thecephalosporin derivative, the composition being administered 1 to 4times per day.

The invention is illustrated, but not limited, by the followingExamples. The n.m.r. spectra are quoted in delta relative totetramethylsilane (delta=0) as internal standard, (s=singlet, d=doublet,t=triplet, q=quartet, m=multiplet, br=broad). The n.m.r. are measured ata field strength of 90 or 400 MHz. The n.m.r. solvents are as follows:

    Solvent A:-d.sub.6 DMSO+CD.sub.3 COOD

    Solvent B:-d.sub.6 DMSO+CD.sub.3 COOD+TFA

    Solvent C:-CDCl.sub.3 +CD.sub.3 COOD

The temperatures are in degrees Centigrade. The following contractionsare used:

    ______________________________________                                        TFA         =     trifluoroacetic acid                                        THF         =     tetrahydrofuran                                             HOAc        =     acetic acid                                                 EtOAc       =     ethyl acetate                                               MeOH        =     methanol                                                    DMF         =     dimethylformamide                                           DMSO        =     dimethylsulphoxide                                          ether       =     diethyl ether                                               HPLC        =     high pressure liquid                                                          chromatography                                              Et.sub.3 N  =     triethylamine                                               Lawesson's reagent                                                                        =     2,4-dithioxo-P.sup.5,P.sup.5 -                                                1,3,2,4-dithia-                                                               phosphatane.                                                MCBPA       =     m-chloroperbenzoic                                                            acid.                                                       DCCI        =     N,N'dicyclohexyl-                                                             carbodi-imide.                                              CAZAMCA     =                                                                  ##STR3##                                                                     BOC         =     tert-butyoxycarbonyl.                                       ______________________________________                                    

EXAMPLES 1-4

To a solution of3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-[(Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylicacid (0.4 mmole) in DMF (11 ml.) and water (3 ml.) at 0° was addedsodium bicarbonate (4.8 mmole) dissolved in the minimum volume of waterfollowed by the appropriate 4-chloroheterocycle (0.4 mmole). After 1hour the mixture was treated with HOAC (4.8 mmole) and evaporated todryness under reduced pressure. The residue was dissolved in water andpurified by HPLC on an octadecylsilane column using MeOH/water/HOAC40:60:1 v/v/v eluant. Using this general method the following compoundswere thus obtained

    ______________________________________                                         ##STR4##                                                                     Example                                                                              R                  Yield %  Footnotes                                  ______________________________________                                                ##STR5##          39       1, 2                                       2                                                                                     ##STR6##          31       3, 4                                       3                                                                                     ##STR7##          33       5, 6                                       4                                                                                     ##STR8##          31       5, 7                                       ______________________________________                                        Footnotes                                                                     1. The starting material was prepared by                                      reaction of 1-phenyl-4-pyridone with                                          toluene- - p-sulphonylchloride in refluxing toluene to                        give 4-chloro-1-phenyl toluene- -p-sulphonate.                                2. n.m.r. in solvent A: 1.5(s, 6H); 3.35                                      (d, 1H); 3.68(d, 1H); 4.3(d, 1H); 4.6(d, 1H); 5.12                            (d, 1H); 5.75(d, 1H); 6.68(s, 1H); 7.1(d, 1H); 7.6(m,                         6H); 8.4(d, 1H); 8.5(d, 1H).                                                  3. The starting material was prepared as                                      follows. A mixture of 2,6-dicarboxy-4-pyrone (1.84 g.)                        and 4-fluoroaniline (1.9 ml.) was heated at 180° under                 argon until evolution of gas ceased. The cooled                               mixture was purified by chromatography on silica gel,                         eluting with CH.sub.2 Cl.sub.2 /MeOH 100-90:0-10 v/v to give, after           sublimation (150°/0.01 mmHg) 1-(4-fluorophenyl)-4-                     pyridone(1.24 g.). n.m.r. in CDCl.sub.3 : 6.45(d, 2H); 7.3                    (m, 4H); 7.54(d, 2H). Reaction of this compound with                          toluene- -p-sulphonylchloride in refluxing toluene gave                       4-chloro-1-(4-fluorophenyl)pyridinium                                         toluene- -p-sulphonate.                                                       4. n.m.r. in solvent A: 1.4(s, 6H); 3.35                                      (d, 1H); 3.65(d, 1H); 4.25(d, 1H); 4.46(d, 1H); 5.1                           (d, 1H); 5.8(d, 1H); 6.7(s, 1H); 6.9-7.8(complex, 6H);                        8.3(d, 1H); 8.5(d, 1H).                                                       5. The starting material was prepared by the                                  method described in Footnote 3, using the appropriate                         substituted aniline.                                                          6. n.m.r. in solvent A: 1.4(s, 6H); 3.36                                      (d, 1H); 3.64(d, 1H); 4.27(d, 1H); 4.48(d, 1H); 5.1                           (d, 1H); 5.8(d, 1H); 6.7(s, 1H); 6.9-7.7(m, 6H); 8.35                         (d, 1H); 8.5(d, 1H).                                                          7. n.m.r. in solvent A: 1.45(s, 6H); 3.4                                      (d, 1H), 3.68(d, 1H); 4.3(d, 1H); 4.5(d, 1H); 5.12                            (d, 1H); 5.85(d, 1H); 6.75(s, 1H); 6.9-7.9(m, 5H); 8.2                        (d, 1H); 8.4(d, 1H).                                                      

The cephalosporin starting material may be obtained as follows:

To a stirred mixture of DMF (5.80 ml.) in anhydrous methylene chloride(415 ml.) at -10° was added dropwise oxalyl chloride (6.15 ml.).Stirring was continued at -10° for 30 minutes to give a gelatinous whiteprecipitate of (chloromethylene)dimethylammonium chloride. To thisstirred suspension was added powdered2-((Z)-1-t-butoxycarbonyl-1-methylethoxyimino)-2-(2-tritylaminothiazol-4-yl)aceticacid (40.0 g.) followed by N-methylmorpholine (8.8 ml.). Stirring wascontinued for 30 minutes between -5° and -15°.

In another flask a suspension of7-amino-3-azidomethylceph-3-em-4-carboxylic acid (17.85 g.) in anhydrousmethylene chloride (150 ml.)was stirred for 1 hour withN,O-bis(trimethylsilyl)acetamide (34.5 ml.) to give a clear orangesolution. This was transferred by syringe to the above acid chloridesolution which was stirred at -10° during the addition. The reactionmixture was then allowed to warm to room temperature and stirred for afurther 90 minutes. The mixture was then poured into water (500 ml.) andextracted with EtoAc (3×500 ml.). The combined EtOAc extracts werewashed with water, dried (Na₂ SO₄) and the solvent was evaporated underreduced pressure to yield a buff foam. The crude product was dissolvedin methylene chloride and applied to a column of Kieselgel 60 (125 g.).Elution with methylene chloride/MeOH/HOAc 96:2:2 v/v/v gave3-azidomethyl-7-[2-(2-tritylaminothiazol-4-yl)-2-((Z)-1-t-butoxycarbonyl-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid (46.4 g.) as a white foam n.m.r. in solvent A:1.30 (s, 9H); 1.35 (s,6H), 3.37 (d, 1H), 3.65 (d, 1H), 3.90 (d,1H), 4.35(d,1H), 5.1 (d,1H); 5.7 (d,1H); 6.66 (s,1H), 7.25 (s,15H).

An aqueous slurry of Raney nickel (10.2 g.) was added in one portion toa stirred solution of the azide (20.0 g.) in a mixture of MEOH (60 ml.)and TFA (60 ml.) at room temperature. A vigorous effervescence wasobserved. Stirring was continued for 1 hour and the Raney nickel wasremoved by filtration through diatomaceous earth. The filter pad waswashed well with MEOH and the washings were combined with the filtrate.The solvents were evaporated under reduced pressure to give a pale greensolid residue which was then stirred for 2 hours with a mixture of TFA(60 ml.) and water (15 ml.). This mixture was evaporated to dryness andthe residue was stirred vigorously with water (400 ml.) for 30 minutes.The resulting solution was filtered through diatomaceous earth to removethe undissolved triphenylmethanol and the filtrate was applied to acolumn of Diaion HP 20 resin (1 l.). The column was eluted with water(500 ml.) to remove inorganic material and then with aqueous MEOH 1:1v/v. The fractions which were shown by HPLC to contain the product wereevaporated under reduced pressure to yield3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylicacid (4.2 g.) as a pale yellow foam having the following n.m.r. insolvent A: 1.4 (s,6H); 3.1-3.8 (complex, 4H); 4.95 (d,1H); 5.7(d,1H);6.72 (s,1H).

EXAMPLES 5-6

The general process described in Examples 1-4 was repeated, and thefollowing compounds were obtained.

    __________________________________________________________________________     ##STR9##                                                                     Example No.                                                                             R           Yield %                                                                            Footnotes                                          __________________________________________________________________________    5         C.sub.2 H.sub.5                                                                           64   1, 2, 3                                                       ##STR10##  55   4, 5                                               __________________________________________________________________________    Footnotes                                                                     1. The starting material may be prepared as follows. Reaction of (            .sub.-- Z)-2-                                                                 ethoxyimino-2-(2-trityl-aminothiazol-4-yl)acetic acid and 7-amino-3-          azidomethyl-ceph-3-em-4-carboxylic acid (previously treated with N,O-         bistrimethylsilylacetamide in the presence of chloromethyleneammonium         chloride and N-methylmorpholine) in CH.sub.2 Cl.sub.2 /DMF gave after         purification by chromatography on silica gel 3-azidomethyl-7-[( .sub.--       Z)-2-                                                                         ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]ceph-3-em-4-carboxylic     acid; n.m.r. in CDCl.sub. 3 : 1.29(t, 3H); 3.3(d, 1H); 3.54(d, 1H);           3.87(d,                                                                       1H), 4.3(q, 2H); 4.38(d, 1H); 4.97(d, 1H); 5.73(q, 1H); 6.72(s, 1H);          7.26                                                                          (m, 15H).                                                                     This 3-azidomethyl compound in TFA acid was reduced with Raney nickel to      give, after purification by chromatography on a Diaion CHP20P                 column, 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-( .sub.-- Z)-2-ethoxyimin    o)-                                                                           acetamido]ceph-3-em-4-carboxylic acid; n.m.r. in solvent A:                   1.2(t, 3H); 3.26(d, 1H); 3.48(br s, 2H); 3.68(d, 1H); 4.08(q, 2H);            4.97(d, 1H),                                                                  5.66(d, 1H); 6.69(s, 1H).                                                     2. The quaternised starting material was 3-chloro-1-methylpyridazinium        iodide.                                                                       3. n.m.r. in solvent A: 1.2(t, 3H); 3.31(d, 1H); 3.61(d, 1H); 4.12(q,         2H);                                                                          4.23(s, 3H); 4.48(d, 1H); 4.99(d, 1H); 5.65(d, 1H); 6.69(d, 1H); 7.6          (m, 1H); 7.9(dd, 1H); 8.88(d, 1H).                                            4. n.m.r. in solvent A: 1.9(m, 2H); 2.45(m, 4H); 3.44(d, 1H); 3.66(d,         1H);                                                                          4.1(d, 1H); 4.28(s, 3H); 4.57(d, 1H); 5.1(d, 1H); 5.82(d, 1H); 6.83           (s, 1H); 7.63(br, 1H); 7.92(br, 1H); 8.9(d, 1H).                              5. The starting material was prepared from 2-[( .sub.-- Z)-                   1-(t-butoxycarbonyl)cyclobut-1-yloxyimino]-2-(2-tritylaminothiazol-4-yl)      acetic acid by the general method described in Footnote 1. to give            3-azido-                                                                      methyl-7-(( .sub.-- Z)-2-[ 1- .sub.- t-butoxycarbonyl)cyclobut-1-             yloxyimino]-2-[2-tritylaminothiazol-4-yl]acetamido)ceph-3-em-4-               carboxylic acid, having the following n.m.r. in solvent A: 1.38(s, 9H);       1.78(m, 1H); 1.89(m, 1H); 2.35(m, 4H); 3.45(d, 1H); 3.63(d, 1H); 3.9(d,       1H); 4.38(d, 1H); 5.13(d, 1H); 5.76(d, 1H); 6.68(s, 1H); 7.18-7.37(m,         15H).                                                                     

The above 3-azidomethylcephalosporin derivative was reduced by thegeneral method described in Footnote 1 to give3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-(Z)-2-(1-carboxycyclobut-1-yloxyimino)acetamido]ceph-3-em-4-carboxylicacid, which was partially purified by chromatography on Diaion CHP20resin before use without further characterisation.

EXAMPLES 7-14

The general process described in Examples 1-4 was repeated using theappropriate heterocyclic starting material. The reactions were carriedout in DMF in the presence of triethylamine or DMF/water mixtures in thepresence of NaHCO₃ at a temperature in the range ambient to 90° for 1-20hours. The product was purified on an octadecylsilane column and thefollowing compounds were thus prepared.

    __________________________________________________________________________     ##STR11##                                                                    Example                                                                             R.sup.1  R.sup.2    Yield %                                                                            Footnotes                                      __________________________________________________________________________     7.   C(CH.sub.3).sub.2 COOH                                                                  ##STR12## 17   1, 2, 3                                         8.   C(CH.sub.3).sub.2 COOH                                                                  ##STR13##  7   4, 2, 5                                         9.   C(CH.sub.3).sub.2 COOH                                                                  ##STR14## 16   6, 7, 8                                        10.   C(CH.sub.3).sub.2 COOH                                                                  ##STR15## 26   9, 2, 10                                       __________________________________________________________________________    Example                                                                             R.sup.1  R          Yield %                                                                            Footnotes                                      __________________________________________________________________________    11    CH.sub.3                                                                                ##STR16## 33   11, 12, 13                                     12    CH.sub.3                                                                                ##STR17## 36   14, 15                                         13    C(CH.sub.3).sub.2 COOH                                                                  ##STR18## 22   16, 17, 18                                     14    C(CH.sub.3).sub.2 COOH                                                                  ##STR19## 20   19, 17, 20                                     __________________________________________________________________________    Footnotes                                                                     1. The starting material was prepared by reaction of 3-chloropyridazine       with trimethyloxonium tetrafluoroborate in CH.sub.2 Cl.sub.2 for 18 hours     to give                                                                       3-chloro-1-methylpyridazinium tetrafluoroborate.                              2. HPLC eluant MeOH/water/HOAc 20:79:1 v/v/v.                                 3. n.m.r. in solvent B: 1.53(s, 3H); 1.52(s, 3H); 3.56(m, 2H); 4.26(s,        3H); 4.1(d,                                                                   1H); 4.6(d, 1H); 5.17(d, 1H); 5.88(d, 1H); 6.94(s, 1H); 7.7(d, 1H);           7.98(dd,                                                                      1H); 8.95(d, 1H).                                                             4. The starting material was prepared by reaction of 3-fluoropyrazine         with                                                                          trimethyloxonium tetrafluoroborate in CH.sub.2 Cl.sub.2 for 4 hours           under reflux to give 1-methyl-3-fluoropyrazinium tetrafluoroborate.           5. n.m.r. in solvent B: 1.53(s, 3H); 1.54(s, 3H); 3.55(m, 2H); 4.21(s,        3H);                                                                          4.2(d, 1H); 4.7(d, 1H); 5.15(d, 1H); 5.85(d, 1H); 7.0(s, 1H); 8.0             (d, 1H); 8.19(s, 1H); 8.6(d, 1H).                                             6. The starting material was obtained as follows. Reaction of 3,6-            dichloropyridazine with trimethyloxonium tetrafluoroborate gave               3,6-dichloro-1-methylpyridazinium tetrafluoroborate. To this compound         (2.0 mmole) in acetonitrile was added NaHCO.sub.3 (2.0 mmole), a few          drops of triethylamine and 2-acetamido-1-mercaptoethane (2.4 mmole).          After 1 hour at ambient temperature the mixture was filtered,                 the filtrate evaporated and ether and CH.sub.2 Cl.sub.2 added. The            product                                                                       crystallised to give 3-chloro-1-methyl-6-(2-acetamidoethylthio)pyridaziniu    tetrafluoroborate.                                                            7. HPLC eluant MeOH/water/HOAc 23:76:1 v/v/v.                                 8. n.m.r. in solvent B: 1.53(s, 1H); 1.54(s, 1H); 3.6(br s, 2H); 3.99(s,      3H);                                                                          4.6(d, 1H); 4.8(d, 1H); 5.17(d, 1H); 5.9(d, 1H); 6.95(s, 1H); 8.16(dd,        2H).                                                                          9. The starting material was obtained by reaction of 4-methoxypyridazine      with trimethyloxonium tetrafluoroborate in CH.sub.2 Cl.sub.2 for 8 hours      at                                                                            ambient temperature to give 4-methoxy-1-methylpyridazinium                    tetrafluoroborate.                                                            10. n.m.r in solvent B: 1.53(br s, 6H); 4.1(s, 3H); 4.39(m, 2H); 5.19(d,      1H);                                                                          5.85(d, 1H); 7.0(s, 1H); 7.37(dd, 1H); 8.55(d, 1H); 8.9(d, 1H).               11. The 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-(( .sub.-- Z)-methoxyim    ino)                                                                          acetamido]ceph-3-em-4-carboxylic acid trifluoroacetate used as starting       material may be prepared as follows: To a solution of cefotaxime (5.24        g.)                                                                           in phosphate buffer (pH 6.4, 440 ml.) was added sodium azide (2.86 g.)        and                                                                           sodium iodide (1.65 g.) and the mixture was immersed in a 70° bath     with                                                                          stirring for 4.5 hours. The solvent was evaporated to the point of            precipita-                                                                    tion and then the pH adjusted to 2.5 with 2N aqueous HCl. The resulting       precipitate was collected, washed with water, acetone and ether and           dried                                                                         over P.sub.2 O.sub.5 to give 3-azidomethyl-7-[2-(2-aminothiazol-4-yl)-2-((     .sub.-- Z)-                                                                  methoxyimino)acetamido]ceph-3-em-4-carboxylic acid in quantative yield,       having the following n.m.r. in solvent A: 3.4(d, 1H); 3.7(d, 1H);             3.86(s,                                                                       3H); 3.95(d, 1H); 4.4(d, 1H); 5.15(d, 1H); 5.78(d, 1H); 6.75(s, 1H).          To a stirred suspension of Raney nickel (16 g.) in MeOH (13 ml.) at           0° was                                                                 added a solution of 3-azidomethyl-7-[2-(2-aminothiazol-4-yl)-2-(( .sub.--     )-                                                                            methoxyimino)acetamido]ceph-3-em-4-carboxylic acid (2.96 g.) in MeOH/         TFA (14 ml., 1.13 ml.). After effervescence ceased the mixture was            diluted                                                                       with MeOH and filtered through paper. The filtrate was evaporated, the        residue purified by HPLC using water/HOAc/MeOH 79:1:20 v/v/v                  as eluant and the product dried over P.sub.2 O.sub.5 to give                  3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-(( .sub.-- Z)-                     methoxyimino)acetamido]ceph-3-em-4-carboxylic acid trifluoroacetate           (yield 45%) having the following n.m.r. in solvent A: 3.5-4.2(m, 4H);         3.9(s, 3H); 5.15(d, 1H); 5.85(d, 1H); 6.75(s, 1H).                            12. HPLC eluant MeOH/water/HOAc 10:89:1 v/v/v.                                13. n.m.r. in solvent B: 3.46(d, 1H), 3.72(d, 1H); 3.97(s, 3H); 4.25(s,       3H);                                                                          4.11(d, 1H); 4.63(d, 1H); 5.13(d, 1H); 5.73(d, 1H); 6.97(s, 1H); 7.57         (d, 1H); 7.98(dd, 1H); 8.93(d, 1H).                                           14. HPLC eluant MeOH/water/HOAc 15:84:1 v/v/v.                                15. n.m.r. in solvent B: 3.43(d, 1H); 3.69(d, 1H); 3.97(s, 3H); 4.19(s,       3H);                                                                          4.23(d, 1H); 4.66(d, 1H); 5.12(d, 1H); 5.69(d, 1H); 7.0(s, 1H); 7.98          (d, 1H); 8.2(s, 1H); 8.6(d, 1H).                                              16. The starting material was prepared by reaction of 3,6-difluoropyridazi    ne                                                                            and trimethyloxonium tetrafluoroborate in CH.sub.2 Cl.sub.2 for 15 hours      at ambient                                                                    temperature to give 3,6-difluoro-1-methylpyridazinium tetrafluoroborate.      This compound in acetonitrile was treated with a solution of ammonia in       chloroform in the presence of 1 equivalent of NaHCO.sub.3 for 0.5 hours       at ambient temperature to give 3-amino-6-fluoro-2-methyl pyridazinium         tetrafluoroborate.                                                            17. HPLC eluant MeOH/water/HOAc 25:74:1 v/v/v.                                18. n.m.r. in solvent B: 1.53(s, 6H); 3.5(m, 2H); 3.7(s, 3H); 3.95(d,         1H); 4.5(d,                                                                   1H); 5.15(d, 1H); 5.8(d, 1H); 7.0(s, 1H); 7.3(s, 2H).                         19. The starting material was prepared by reaction of 2,5-dimethyl-3-fluor    o-                                                                            pyrazine and trimethyloxonium tetrafluoroborate in CH.sub.2 Cl.sub.2 at       ambient                                                                       temperature for 5 hours to give 3-fluoro-1,2,5-trimethylpyrazinium            tetrafluoroborate.                                                            20. n.m.r. in solvent B: 1.53(s, 6H); 2.38(s, 3H); 2.53(s, 3H); 3.5(m,        2H); 4.1(s,                                                                   3H); 4.2(d, 1H); 4.85(d, 1H); 5.1(d, 1H); 5.85(d, 1H); 7.05(s, 1H);           7.9(s, 1H).                                                               

EXAMPLES 15-16

The general process described in Examples 7-14 was repeated using theappropriate 3-aminomethylcephalosporin derivative and the appropriatechloroheterocycle and the following compounds were obtained.

    __________________________________________________________________________     ##STR20##                                                                    Example R               Yield %                                                                              Footnotes                                      __________________________________________________________________________    15                                                                                     ##STR21##      35     1                                              16      CH.sub.2 CH.sub.2 Br                                                                          11     2                                              __________________________________________________________________________    Footnotes                                                                     1. n.m.r. in solvent A: 2.68(s, 3H); 3.6(m, 4H); 4.0-4.8(m, 4H); 4.25(s,      3H);                                                                          5.15(d, 1H); 5.81(d, 1H); 7.0(s, 1H); 7.61(d, 1H); 7.99(dd, 1H); 8.97(d,      1H).                                                                          2. n.m.r. in solvent A: 3.6-3.9(m, 4H); 4.0-4.6(m, 4H); 4.26(s, 3H);          5.14(d, 1H);                                                                  5.82(d, 1H); 6.97(s, 1H); 7.65(d, 1H); 8.02(dd, 1H); 9.0(d,                   __________________________________________________________________________    1H).                                                                      

The starting materials for use in the above process may be obtained asfollows:

Reaction of ethyl2-(2-tritylaminothiazol-4-yl)-2-((Z)-2-bromoethoxyimino)acetate (UKpatent application 2017702A) with 2-mercapto-5-methyl-1,3,4-thiadiazoleand hydrolysis of the ester gave2-(2-tritylaminothiazol-4-yl)-2-[(Z)-2-(5-methyl-1,3,4-thiadiazol-2-ylthio)ethoxyimino]aceticacid; n.m.r. in solvent C: 2.7 (s,3H); 3.65 (t,2H); 4.51 (t,2H); 6.65(s,1H); 7.34 (s,15H).

Triethylamine (1.0 mmole.) and phosphorus pentachloride (1.0 mmole) wereadded to a solution of2-(2-tritylaminothiazol-4-yl)-2-[(Z)-2-(S-methyl-1,3,4-thiadiazol-2-ylthio)ethoxyimino]aceticacid (1.0 mmole) in CH₂ Cl₂ (2.5 ml.) under argon at 0° and the mixturestirred for 1.5 hours. The solvent was evaporated and the residuedissolved in CH₂ Cl₂. To this solution was added a solution of7-amino-3-azidomethylceph-3-em-4-carboxylic acid (1.0 mmole.) in CH₂ Cl₂(2.5 ml.) under argon [this solution having been previously treated at0° with N,O-bistrimethylsilylacetamide (2.0 mmole.) and allowed to warmto ambient temperature over 2 hours]. After 1.5 hours the mixture wasdiluted with CH₂ Cl₂ and the organic layer washed with water, brine anddried (MgSO₄). Evaportion of the solvent and purification of the residueby chromatography on silica gel gave the product. Using this generalprocess the following compounds were prepared.

    __________________________________________________________________________     ##STR22##                                                                    R                         Footnotes                                           __________________________________________________________________________     ##STR23##                1                                                   CH.sub.2 CH.sub.2 Br      2, 3                                                __________________________________________________________________________    Footnotes                                                                     1. n.m.r. in solvent A: 2.68(s, 3H); 3.64(m, 4H); 3.92(d, 1H); 4.46(d,        1H);                                                                          4.48(m, 2H); 5.2(d, 1H); 5.8(d, 1H); 6.92(s, 1H); 7.37(s, 15H).               2. The starting material was 2-(2-tritylamino-thiazol-4-yl)-2-(( .sub.--      Z)-2-                                                                         bromoethoxyimino)acetic acid (UK patent application 2017702A).                3. n.m.r. in solvent A: 3.5-3.9(m, 4H); 4.2-4.5(m, 4H); 5.16(d, 1H);          5.76(d, 1H);                                                                  6.8(s, 1H); 7.34(s, 15H).                                                 

The 3-azidomethylcephalosporin derivative was dissolved in formic acidand treated with an excess of wet Raney nickel for 50 minutes. Themixture was filtered through diatomaceous earth and the pad rinsed withMeOH/water 1:1 v/v. The filtrate was evaporated and the residuedissolved in TFA/water 9:1 v/v (5 ml.) at ambient temperature. After 1.5hours the solvent was evaporated and the residue purified bychromatography on Diaion HP 20 resin, eluting with increasingproportions of MeOH in water. There were thus obtained the followingcompounds.

    ______________________________________                                         ##STR24##                                                                    R                       Footnotes                                             ______________________________________                                         ##STR25##              1                                                     CH.sub.2 BH.sub.2 Br    2                                                     ______________________________________                                        Footnotes                                                                     1. n.m.r. in solvent A: 2.67(s, 3H); 3.62                                     (m, 6H); 4.47(t, 2H); 5.15(d, 1H); 5.86(d, 1H); 7.0                           (s, 1H).                                                                      2. n.m.r. in solvent A: 3.65-3.9(m, 6H); 4.42                                 (t, 2H); 5.17(d, 1H); 5.88(d, 1H); 6.97(s, 1H).                           

EXAMPLE 17

To a solution of3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylicacid (400 mg.) and 4-chloro-1,7-dimethyl-1,8-naphthyridiniumtetrafluoroborate (190 mg.) in DMF (2 ml.) was added triethylamine (285ul.) at ambient temperature. After 1 hour the solvent was evaporated andthe residue purified by HPLC on an octadecylsilane column usingMeOH/aqueous ammonium carbonate (2 g./l) 30:70 v/v as eluant to give thefollowing compound ##STR26## in 10% yield, n.m.r. in solvent B: 1.5(s,6H); 2.73 (s,3H); 3.6 (s,2H); 4.1 (s,3H); 4.65 (s,2H), 5.2 (d,1H);6.9 (d,1H), 7.0 (s,1H); 7.0 (d,1H); 7.7 (d,1H); 8.8 (dd,1H).

The starting material may be obtained as follows.3-Carboxy-4-hydroxy-7-methyl-1,8-naphthyridine was heated at 300° in atube equipped with a cold finger to give4-hydroxy-7-methyl-1,8-naphthyridine. Reaction of this compound withphosphorous oxychloride at 100° for 30 minutes gave4-chloro-7-methyl-1,8-naphthyridine. Reaction of this compound withtrimethyloxonium tetrafluoroborate in CH₂ Cl₂ at ambient temperature for3 hours gave, after evaporation of solvent and washing of the residuewith ether, 4-chloro-1,7-dimethyl-1,8-naphthyridinium tetrafluoroboratewhich was used without further purification.

EXAMPLES 18-24

The following compounds were prepared by reaction of3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylicacid with the appropriate quaternary heterocycle in the manner describedin Example 1.

    ______________________________________                                         ##STR27##                                                                    Exam-                        Yield   Foot-                                    ple   R                      (%)     notes                                    ______________________________________                                               ##STR28##             22      1                                               ##STR29##             27      2, 3                                     20.                                                                                  ##STR30##             40      4, 5                                            ##STR31##             14      6, 7                                            ##STR32##             13      8, 9                                            ##STR33##             14      10, 11                                          ##STR34##             16      12, 13                                   ______________________________________                                        Footnotes                                                                     1. N.m.r. in solvent A: 1.42(s, 6H), 2.52(s, 3H), 2.7(s, 3H), 3.68(dd,        2H), 4.42(d, 1H), 4.8(d, 1H) 5.12(d, 1H), 5.9(d, 1H), 7.0(s, 1H),             7.82(m, 1H), 8.1(d, 1H).                                                      2. N.m.r. in solvent A: 1.42(s, 6H), 3.32(d, 1H), 3.61(d, 1H),                4.22(d, 1H), 4.61(d, 1H), 5.05(d, 1H), 5.76(d, 1H), 6.72(s,                   1H) 7.02(d, 1H), 7.78(d, 1H), 8.1(d, 1H), 8.7(d, 1H).                         3. The staring material may be prepared as follows: Lawesson's                reagent (5.26 g.) was added to a boiling solution of                          8H-thiazolo[3,2-a]pyrimidin-7-one (4.0 g.) in CH.sub.3 CN                     (200 ml.) and the mixture was heated under reflux with stirring               for 1.5 h. On cooling silica gel (70-230 mesh, 15 g.) was added               and the mixture was evaporated to dryness. The residue was                    applied to a column of silica gel (300 g.) and eluted with                    MeOH/CH.sub.2 Cl.sub.2  (5-10%) to give 8H-thiazolo[3,2-a]-                   pyrimidin-7-thione (2.7 g.). Trimethyloxonium tetrafluoroborate               (2.0 g.) was added to a stirred suspension of 8H-thiazolo[3,2-a]-             pyrimidin-7-thione (1.5 g.) in dry CH.sub.3 CN (50 ml.). After                stirring for 2 h, the solution was concentrated to about 20 ml.,              and with vigorous stirring anhydrous ether (100 ml.) was added                to precipitate 7-methylthiothiazolo[3,2-a]pyrimidinium                        tetrafluoroborate (1.3 g.), having nmr in d.sub.6 DMSO: 2.78(s, 3H),          8.04(d, 1H), 8.22(d, 1H), 8.55(d, 1H), 9.24(d, 1H).                           4. N.m.r. in solvent A: 1.42(s, 6H), 3.5(d, 2H) 3.68(m, 2H), 4.18(d,          1H), 4.6(m, 3H), 5.1(d, 1H), 5.82(d, 1H), 6.62(d, 1H), 6.72(s, 1H),           8.12(d, 1H).                                                                  5. Starting from 2,3-dihydro-8H-thiazolo[3,2-a]pyrimidin-7-one,               2,3-dihydro-7-methylthiothiazolo[3,2-a]pyrimidinium                           tetrafluoroborate was prepared in the same way as described in                footnote 3.                                                                   6. N.m.r. in solvent A: 1.42(s, 6H), 3.58(dd, 2H), 4.25(d, 1H),               4.75(d, 1H), 5.1(d, 1H), 5.82(d, 1H), 6.75(s, 1H), 7.39(s, 1H),               7.6(d, 1H), 9.21(s, 1H).                                                      7. Starting from 5-methoxycarbonyl-8H-thiazolo[3,2-a]-                        pyrimidin-7-one, 5-methoxycarbonyl-7-methylthiothiazolo[3,2-a]-               pyrimidinium tetraborate was prepared in the same way as                      described in footnote 3. Upon reaction with the amino-                        methylcephalosporin, as described in Example 1, this material                 underwent hydrolysis of the methyl ester in addition to                       displacement of the methylthio group.                                         8. N.m.r. in solvent A: 1.12(t, 3H), 1.42(s, 6H), 2.7(s, 2H),                 3.3(d, 1H), 3.58(d, 1H), 4.2(d, 1H), 4.6(d, 1H), 5.09(d, 1H),                 5.68(d, 1H), 6.66(s, 1H), 8.0(d, 1H), 8.1(s, 1H), 9.18(d, 1H).                9. The starting material may be prepared as follows:                          2-Amino-5-ethoxycarbonylmethylthiazole (3.72 g.), ethyl                       propiolate (1.96 g.) and 25% aqueous tetramethylammonium                      hydroxide (0.15 ml.) in absolute EtOH (50 ml). were heated under              reflux for 16 h. The solution was concentrated and the residue                purified by column chromatography (silica gel; 10%                            MeOH/CH.sub.2 Cl.sub.2) to give 3-ethoxycarbonylmethyl-8H-                    thiazolo[3,2-a]pyrimidin-7-one (1.6 g.), as a solid having                    nmr in d.sub.6 DMSO: 1.2(t, 3H), 4.1(m, 4H), 6.15(d, 1H),                     7.15(s, 1H), 8.18(d, 1H). This material was converted to                      3-ethoxycarbonylmethyl-7-methylthiothiazolo[3,2-a]pyrimidinium                tetrafluoroborate in the same way as described in footnote 3.                 10. N.m.r. in solvent A: 1.4(s, 6H), 3.35(d, 1H), 3.65(d, 1H),                4.32(d, 1H), 4.65(d, 1H), 5.05(d, 1H), 5.78(d, 1H), 6.75(s, 1H),              7.12(d, 1H), 7.7(m, 2H), 8.25(m 1H), 9.23(d, 1H).                             11. 1H-Benzo[4,5]thiazolo[3,2-a]pyrimidin-2-one was converted to              2-methylthiobenzo[4,5]thiazolo[3,2-a]pyrimidinium tetra-                      fluoroborate in the same was as described in footnote 3.                      12. N.m.r. in solvent A: 1.4(s, 6H), 2.75(s, 3H) 3.35(d, 1H), 3.61(d,         1H), 4.28(d, 1H) 4.68(d, 1H), 5.04(d, 1H). 5.78(d, 1H), 6.72(s, 1H),          7.03(d, 1H), 8.98(d, 1H).                                                     13. 8H-2-Methyl-1,3,4-thiadiazolo[3,2-a]pyrimidin-7-one was                   converted to 2-methyl-7-methylthio-1,3,4-thiadiazolo[3,2-a]-                  pyrimidinium tetrafluoroborate in the same way as described in                footnote 3.                                                               

EXAMPLES 25-28

To a stirred suspension of 3-aminomethyl-7-[2-(2aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4carboxylic acid (200 mg.-0,4 mmole) and triethylamine (120 μl. - 0.8mmole) in DMF(2 ml.) at 25° C. was added to the appropriateN-alkylated-4-methylthio pyrimidinium salt (0.6 mmole).

After 30 minutes, the solution was evaporated to dryness under reducedpressure and the residue purified by preparative HPLC (octadecyl silanecolumn).

Using this general process and the appropriate quaternised heterocyclethe following compounds were obtained.

    __________________________________________________________________________     ##STR35##                                                                    Examples                                                                             R               Yield (%)                                                                           Footnotes                                        __________________________________________________________________________            ##STR36##      67    1    2                                                   ##STR37##      25    3    4                                                   ##STR38##      24    5    6                                                   ##STR39##      25    7    8                                           __________________________________________________________________________    Footnotes                                                                     1. N.m.r. in solvent B: 1.54(s, 6H), 3.60 (m, 2H), 4.3(d, 1H), 4.8(d,         1H), 5.2(br, 1H),                                                             5.3(s, 2H), 5.9(br, 1H), 7.0(d, 1H), 7.1(s, 1H), 7.5(s, 1H), 8.3(s, 1H),      9.0(s, 1H).                                                                   2. The pyrimidinium salt may be prepared as follows: A suspension of          4-methylthio-                                                                 pyrimidine (350 mg. 2.8 mmole) and alkyl halide (2.8 mmole) was heated at     80° C.                                                                 for 1 hour. The residue was triturated with EtOAc and the resulting solid     filtered                                                                      off. N.m.r. in solvent B: 2.52(s, 3H), 5.6(s, 2H), 7.5(s, 1H), 8.1(d,         1H), 9.0(d, 1H),                                                              9.62(s, 1H).                                                                  3. N.m.r. in solvent B: 1.54(s, 6H), 3.6(m, 2H), 4.3(d, 1H), 4.8(d, 1H),      5.0(d, 2H);                                                                   5.2(d, 1H), 5.9(d, 1H), 6.8(s, 1H), 7.05(m, 3H), 7.45(m, 5H), 8.3(d, 1H),     8.95(s, 1H).                                                                  4. The starting material may be prepared in the same way as described in      footnote                                                                      2. N.m.r in solvent B: 2.74(s, 3H), 5.36(d, 2H), 6.8(m, 2H), 7.4(m, 5H),      8.12(d, 1H),                                                                  8.93(d, 1H), 9.6(s, 1H).                                                      5. N.m.r. in solvent B: 1.54(s, 6H), 3.56(m, 2H), 4.3(d, 1H), 4.8(d, 1H),     5.2(d, 1H),                                                                   5.6(s, 2H), 5.9(d, 1H) 7.0(m, 2H), 7.05(s, 1H), 7.24(s, 1H), 7.46(d, 1H),     8.2(d, 1H),                                                                   9.0(s, 1H).                                                                   6. The starting material may be prepared in the same was as described in      footnote 2.                                                                   N.m.r. in solvent B: 2.74(s, 3H), 5.87(s, 2H), 6.9-7.8(m, 3H), 8.06(d,        1H),                                                                          8.95(d, 1H), 9.6(s, 1H).                                                      7. N.m.r. in solvent B: 1.54(s, 6H), 3.6(m, 2H), 4.4(d, 1H), 4.8(d, 1H),      5.2(d, 1H),                                                                   5.8(s, 2H), 5.95(d, 1H), 7.04(d, 1H), 7.15(s, 1H), 7.7(s, 2H), 8.3(d,         1H), 9.0(s, 1H).                                                              8. The starting material may be prepared in the same way as described in      footnote                                                                      2. N.m.r. in solvent B: 2.74(s, 3H), 6.12(s, 2H), 7.7(s, 2H), 8.3(d,          1H),                                                                          9.1(d, 1H), 9.7(s, 1H).                                                   

EXAMPLE 29 ##STR40##

To a stirred suspension of3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-methoxyimino)acetamido]ceph-3-em-4-carboxylicacid (205 mg.-0.5 mmole) and triethylamine (70 μl. 0.5 mmole) in DMF (2ml.) at 25° C. was added the quaternised pyrimidine described in Example28, footnote 8 (185 mg. 0.5 mmole). After 30 min the solution wasevaporated to dryness and the residue was purified by preparative HPLC(octecycl silane column). Yield 33%. N.m.r. in solvent B: 3.6 (m, 2H),4.0 (s, 3H), 4.3 (d, 1H), 4.8 (d, 1H), 5.15 (m, 1H), 5.85 (br, 3H), 7.05(m, 2H), 7.7 (s, 2H), 8.3 (d, 2H), 9.0 (s, 1H).

EXAMPLE 30 ##STR41##

To a stirred suspension of3-ethylaminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylicacid (160 mg. 0.31 mmole) and triethylamine (85 μl - 0.62 mmole) in DMF(2 mi.) at 25° C. was added the N-alkylated-4-methylthiopyrimidine (140mg. 0.62 mmole).

To a stirred suspension of3-ethylaminomethyl-7-[92-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylicacid (160 mg. 0.31 mmole) and triethylamine (85 μl - 0.62 mmole) in DMF(2 ml.) at 25° C. was added the N-alkylated-4-methylthiopyrimidine (140mg. 0.62 mmole). After 2 hr. at 45° C., the solution was evaporated todryness and the residue was purified by preparative HPLC.

N.m.r. in solvent B: 1.16 (m, 3H), 1.54 (s, 6H), 3.6 (m, 4H), 4,6-5.3(m, 5H), 5.9 (d, 1H), 7.05 (s, 1H), 7.2 (m, 1H), 8.3 (d, 1H), 8,8 (s,1H).

The starting material may be prepared as follows:

A suspension of 4-methylthiopyrimidine (504 mg. 4 mmoles) and2-chloroacetamide (375 mg. 4 mmoles) was heated at 90° C. for 3 hr. Thereaction mixture was triturated with EtOAc, and the resulting solid wasfiltered off.

N.m.r. in solvent B: 2.52 (s, 3H), 5.2 (s, 2H), 8.1 (d, 1H), 8.8 (d,1H), 9.3 (s, 1H).

EXAMPLES 31-32

The process described in Example 29 was repeated, using3-ethylaminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-2-chloroethoxyimino)acetamido]ceph-3-em-4-carboxylicacid as starting material, to give the following compounds:

    ______________________________________                                         ##STR42##                                                                    Example                                                                              R                 Yield (%) Footnotes                                  ______________________________________                                                ##STR43##        12        1, 2, 3                                            ##STR44##        31        1, 2, 4                                    ______________________________________                                        Footnotes                                                                     1. To a solution of 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-               ((Z)-2-chloroethoxyimino)acetamido]ceph-3-em-4-carboyxlic acid.               (2 g. 4.3 mmoles) in MeOH (120 ml.) was added triethylamine                   (0.6 ml. 4.3 mmoles) and sodium cyanoborohydride (0.14 g.                     2.2 mmoles). After addition of acetaldehyde (0.15 ml. 2.2                     mmoles) the mixture was stirred at room temperature for 1 hour.               After evaporation the residue was purified on HP20 resin. N.m.r.              in solvent B: 1.21(s, 3H), 2.8-3.1(m, 2H), 3.2-4.2(m, 6H),                    4.2-4.6(m, 2H), 5.4(d, 1H), 5.8(d, 1H), 7.1(s, 1H).                           2. The above 3-ethylaminomethyl cephalosporin was reacted with                the appropriate quaternised heterocycle in the same way as                    described in Example 30.                                                      3. N.m.r. in solvent B: 1.2(br, 3H), 3.5(br, 4H), 3.85(s, 3H),                4.0(br, 2H), 4.5(m, 4H), 5.3(d, 1H), 5.9(d, 1H), 7.05(s, 1H), 7.4(d,          1H), 7.8(d, 1H).                                                              4. N.m.r. in solvent B: 1.2(br, 3H), 3.0-4.0(m, 6H), 4.2-5.3(m, 7H),          5.85(d, 1H), 7.04(s, 1H), 7.2(d, 1H), 8.3(d, 1H) 8.7(s, 1H).              

EXAMPLES 33-34

The process described in Example 25 was repeated, using the appropriatemethylthio heterocycle, to give the following compounds.

    ______________________________________                                         ##STR45##                                                                    Example R              Yield (%)   Footnotes                                  ______________________________________                                                 ##STR46##     42%         1, 2                                                ##STR47##     14%         3, 4                                       ______________________________________                                        1. N.m.r. in solvent B: 1.55(s, 6H), 3.6(m, 2H), 4.02(s, 3H),                 4.7(d, 1H), 5.1(d, 1H), 5.2(d, 1H), 5.9(d, 1H), 7.05(s, 1H),                  7.9(m, 1H), 9.1(m, 3H).                                                       2. The starting material may be obtained as follows: 4-Methylthio-            pyrido[2,3-d]pyrimidine (700 mg. 4 mmoles) was reacted with                   trimethyloxonium tetrafluoroborate (582 mg. 4 mmoles) in                      CH.sub.2 Cl.sub.2 (20 ml.) at ambient temperature for 1 hr. After             filtration the solvent was evaporated to give a solid which was               used without further purification.                                            3. N.m.r. in solvent B: 1.55(s, 6H), 3.65(br, 2H), 4.37(s, 3H), 4.6(d,        1H), 5.0(d, 1H), 5.2(d, 1H), 5.9(d, 1H), 7.0(s, 1H), 8.0(m, 1H),              8.8(s, 1H), 9.45(m, 2H).                                                      4. The solid obtained in footnote 2 was used after trituration                in MeOH.                                                                  

EXAMPLE 35 ##STR48##

To a stirred suspension of 3-aminomethyl-7-[2-(2aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylicacid (200 mg.-0.4 mmole) and triethylamine (120 μl. - 0.8 mmole) in DMF(2 ml.) at 25° C. was added the N-alkylated-4-methylthio heterocycle(0.6 mmole). After 30 min., the solution was evaporated to dryness underreduced pressure and the residue purified by preparative HPLC (octadecylsilane column).

N.m.r. in solvent B: 1.54 (s, 6H), 3.6 (m, 2H), 4.35 (d, 1H), 4.8 (d,1H), 5.2 (d, 1H), 5.8 (s, 2H), 5.9 (d, 1H), 7.0 (m, 4H), 7.9 (d, 2H),8.1 (d, 1H), 8.7 (s, 1H).

The methylthio heterocycle used as starting material may be prepared inthe same way as described in Example 25, footnote 2.

N.m.r. in solvent B: 2.75 (s, 3H), 6.14 (s, 2H), 7.0 (d, 2H), 8.0 (d,2H), 8.2 (d, 1H), 8.8 (d, 1H), 9.4 (s, 1H).

EXAMPLES 36-37

The process described in Example 30 was repeated, using the appropriatemethylthio heterocycle as starting material, to give the followingcompounds:

    ______________________________________                                         ##STR49##                                                                    Exam-                                                                         ple   R                  Yield (%) Footnotes                                  ______________________________________                                               ##STR50##         46%       1, 2                                              ##STR51##         46%       3, 4                                       ______________________________________                                        Footnotes:                                                                    N.m.r. solvent B: 1.52(s, 9H), 3.51(s, 2H), 4.0(s, 5H), 4.95(d, 1H),          5.2(m, 2H), 5.9(d, 1H), 7.0(s, 1H), 7.9(m, 1H), 8.7(d, 1H), 9.1(m, 2H).       2. The starting material was described in Example 33, footnote 2.             3. N.m.r in solvent B: 1.13(m, 3H), 1.53(s, 6H), 3.2-3.9(m, 4H),              4.6(d, 1H), 4.8-5.3(m, 2H), 5.6(s, 2H), 5.85(d, 1H), 6.9-7.6(m,               5H), 8.4(d, 1H), 9.0(s, 1H).                                                  4. Starting material described in Example 27, Footnote 6.                 

EXAMPLE 38 ##STR52##

The general process described in Example 27 was repeated, using theappropriate 4-methylsulphinyl pyridinium salt.

N.m.r. in solvent B: 1.54 (s, 6H), 2.5 (br, 2H), 2.8 (br, 2H), 3.55 (m,2H), 4.35 (br, 2H), 5.2 (d, 1H), 5.7 (m, 1H), 5.9 (d, 1H), 7.0 (m, 4H),8.2 (m, 2H).

The pyridinium salt was used as starting material may be obtained bycondensation of the known 4-methylthiopyridine and3-bromo-1-cyanocyclopentene in MeOH at 20° C. for 12 hr.

N.m.r. in solvent B: 2,3-3.0 (m, 7H), 5.8 (br, 1H), 6.7 (s, 1H), 7.6 (d,2H), 8.5 (d, 2H).

This product, as its tetrafluoroborate salt, was oxidised with MCPBA inCH₂ Cl₂ /TFA at 20° C. for 3 hr. After evaporation of the solvents thesolid was triturated with ether and used without further purification.

EXAMPLES 39-53

A solution of NaHCO₃ (0.6 mM) in water (750 ml.) was added to a solutionof 7-acyl-3-aminomethyl- cephalosporin derivative (0.2 mM) in DMF (2ml.), followed after a few minutes by the appropriate quaternisedheterocyclic starting material (0.22 mM). The mixture was stirred atroom temperature during 3hrs. The mixture was evaporated to dryness andthe residue purified by HPLC on an octadecylsilane column.

Using this general process the following compounds were prepared.

    __________________________________________________________________________     ##STR53##                                                                                                       Yield                                      Example                                                                            R.sub.1    R.sub.2            (%) Footnotes                              __________________________________________________________________________    39.  CH.sub.2 CHCHCO.sub.2 H                                                                   ##STR54##         36  1, 2                                   40.  CH.sub.2 CH.sub.2 SOCH.sub.3                                                              ##STR55##         32  3, 4                                   41.  CH.sub.2 CH.sub.2 SO.sub.2 CH.sub.3                                                       ##STR56##         59  5, 6                                   42.  CH.sub.2 CH.sub.2 SOCH.sub.3                                                              ##STR57##         32  7, 8                                   43.  CH.sub.2 CN                                                                               ##STR58##         37  9, 10                                  44.  CH.sub.2 CN                                                                               ##STR59##         49  11, 12                                 45.  CH.sub.2 CH.sub.2 F                                                                       ##STR60##         40  13, 14                                       ##STR61##                                                                                ##STR62##         37  15, 16                                       ##STR63##                                                                                ##STR64##         55  17, 18                                 48.  CH.sub.2 CH.sub.2 F                                                                       ##STR65##         21  19, 20                                 49.  CH.sub.2 CF.sub.3                                                                         ##STR66##         4   21, 22                                 50.  CH.sub.2 CF.sub.3                                                                         ##STR67##         48  23, 24                                 51.  CH.sub.2 CF.sub.3                                                                         ##STR68##         31  25, 26                                       ##STR69##                                                                                ##STR70##         30  27, 28                                 53.  CH.sub.2 CH.sub.2 F                                                                       ##STR71##         52  29, 30                                 __________________________________________________________________________    1. Reaction time: 1 Hour 40 minutes.                                          2. N.m.r. in solvent B: 3.35-3.85(m, 2H), 4.3(s, 3H), 4.1-4.5(m, 2H),         4.8(d, 2H), 5.2(d, 1H),                                                       5.9(d, 1H), 6.1(d, 1H), 7.05(s, 1H), 6.8-7.2(m, 1H), 7.8-9.1(m, 4H).          3. The process was carried out using 3-aminomethyl-7-[2-(2-aminothiazol-4-    yl)-2-(Z-methylthio-                                                          ethoxyimino)acetamido]ceph-3-em-4-carboxylic acid and 3-chloro-1-methyl-py    ridinium iodide,                                                              during 2 hours. The crude product was not purified after evaporation but      was oxidised directly as                                                      follows: A solution of crude 7-[2-(2-aminothiazol-4-yl)-2-(Z-methylthioeth    oxyimino)acetamido]-                                                          3-(1-methyl-3-pyridazinio)aminomethylceph-3-em-4-carboxylic acid (0.5 mM)     in TFA (4.0 ml.)                                                              and CH.sub.2 Cl.sub.2 (6.0 ml.) was cooled to -25° C. with             vigourous stirring                                                            m-chloroperbenzoic acid (0.5 mM) was added portion wise during 1 hr. The      temperature was                                                               allowed to rise to ambient, the mixture was evaporated to dryness and the     residue was purified                                                          by HPLC on an octadecylsilane column.                                         4. N.m.r. in solvent B: 2.6(s, 3H), 3.2(d, 2H), 3.6(dd, 2H), 4.3(s, 3H),      4.6(m, 4H), 5.2(d, 1H),                                                       5.8(d, 1H), 7.1(s, 1H), 7.65(d, 1H), 8.0(dd, 1H) 8.9(d, 1H).                  5. Reaction time: 1 Hour 45 minutes.                                          6. N.m.r. in solvent B: 2.9(s, 3H), 3.5-3.7(m, 4H), 4.2(s, 3H),               4.5-4.7(m, 4H), 5.1(d, 1H),                                                   5.57, (d, 1H), 7.05(s, 1H), 7.55(d, 1H), 8.0(dd, 1H), 9.0(d, 1H).             7. Prepared in two stages, condensation and oxidatin as in footnote 3.        Reaction time for the                                                         condensation: 4 hours 30 minutes at 50° C.                             8. N.m.r. in solvent B: 2.61(s, 3H), 3.2(d, 2H), 3.9(s, 5H), 4.7(m, 4H),      5.2(d, 1H), 5.9(d, 1H),                                                       7.05(s, 1H), 7.65(d, 1H), 7.75(d, 1H).                                        9. Reaction time: 2 hours 30 minutes at 50° C.                         10. N.m.r. in solvent B: 3.53(m, 2H), 3.7(s, 3H), 4.23(m, 2H), 5.08(s,        2H), 5.2(d, 1H), 5.77(d, 1H)                                                  7.08(s, 1H), 7.34(s, 2H).                                                     11. Reaction time: 2 hours.                                                   12. N.m.r. in solvent B: 3.51(m, 2H), 4.52(m, 2H), 5.05(s, 2H), 5.11(d,       1H), 5.75(s, 2H), 5.8(d, 1H)                                                  7.0(d, 1H), 7.17(s, 1H), 7.78(s, 2H), 8.24(d, 1H), 8.96(s, 1H).               13. Reaction temperature: 50° C.                                       14. N.m.r. in solvent B: 3.5(m, 2H), 3.7(s, 3H), 3.8-4.6(m, 5H), 4.9(m,       1H), 5.15(d, 1H),                                                             5.78(d, 1H), 6.99(s, 1H), 7.3(s, 2H).                                         15. Reaction temperature: 50° C.                                       16. N.m.r. in solvent B: 3.6(m, 2H), 3.72(s, 3H), 4.3(dd, 2H), 5.15(d,        1H), 5.43(s, 2H),                                                             5.8(d, 1H), 7.06(s, 1H), 7.33(s, 2H), 7.73(s, 2H).                            17. Reaction time: 45 minutes at 50° C.                                18. N.m.r. in solvent B: 3.55(m, 2H), 4.5(dd, 2H), 5.05(d, 1H), 5.45(s,       2H), 5.8(d, 1H), 7.0(d, 1H),                                                  7.05(s, 1H), 7.65(d, 2H), 7.7(d, 1H), 8.05(d, 1H), 8.80(d, 1H).               19. Reaction time: 20 hours.                                                  20 N.m.r. in solvent B: 3.5(m, 2H), 4.1-4.8(m, 5H), 4.9(m, 2H), 5.13(d,       1H), 5.81(d, 1H),                                                             7.01(d, 1H), 7.02(s, 1H), 7.65(d, 1H), 8.11(d, 1H), 8.74(d, 1H).              21. Reaction time: 1 hour.                                                    22. N.m.r. in solvent B: 3.42(d, 1H), 3.68(d, 1H), 4.07(s, 3H), 4.57(d,       1H), 4.95(d, 1H), 4.64(d,                                                     1H), 4.82(d, 1H), 5.12(d, 1H), 5.77(d, 1H), 7.07(s, 1H), 7.91(s, 2H),         8.85(s, 1H).                                                                  23. Reaction time: 1 hour.                                                    24. N.m.r. in solvent B: 3.57(d, 1H), 3.65(d, 1H), 3.67(t, 2H), 4.18(d,       1H), 4.4-4.9(m, 5H),                                                          5.11(d, 1H), 5.78(d, 1H), 6.61(d, 1H), 7.0(s, 1H), 8.15(d, 1H).               25. Reaction time: 2 hours 30 minutes at 50° C.                        26. N.m.r. in solvent B: 3.4(d, 1H), 3.62(d, 1H), 3.68(s, 3H), 3.95(d,        1H), 4.42(d, 1H),                                                             4.63(d, 1H), 4.82(d, 1H), 5.11(d, 1H), 5.74(d, 1H), 7.0(s, 1H), 7.3(s,        2H).                                                                          27. Reaction time: 2 hours at 50° C.                                   28. N.m.r. in solvent B: 3.25(m, 2H), 3.6(s, 3H), 4.0(dd, 2H), 4.8(d,         1H), 5.15(s, 2H), 5.5(d, 1H),                                                 6.65(s, 1H), 7.15(d, 1H), 7.4(d, 2H), 8.25(m, 3H).                            29. Reaction time: 20 hours.                                                  30. N.m.r. in solvent B: 3.55(m, 2H), 4.2-4.9(m, 5H), 4.98(t, 1H),            5.19(d, 1H), 5.39(s, 2H),                                                     5.81(d, 1H), 7.02(s, 1H), 7.0-7.3(m, 2H), 7.38(d, 2H), 7.68(d, 2H),           8.3-8.7(m, 2H).                                                           

The cephalosporin starting materials for use in the above process areobtained by the method described above.

Using this general process the following compounds were prepared.

    ______________________________________                                         ##STR72##                                                                    R                  Footnotes                                                  ______________________________________                                        CH.sub.2 CHCHCO.sub.2 t-Bu                                                                       1, 2                                                       CH.sub.2 CH.sub.2 SCH.sub.3                                                                      3, 4                                                       CH.sub.2 CH.sub.2 SO.sub.2 CH.sub.3                                                              5, 6                                                       CH.sub.2 CN        7                                                          CH.sub.2 CH.sub.2 F                                                                              8, 9                                                        ##STR73##         10, 11, 12, 13                                             CH.sub.2 CF.sub.2  14, 15, 16, 13                                              ##STR74##         17, 18, 15, 13                                             ______________________________________                                         Footnotes                                                                    1. The starting material was prepared by reaction of 4-nitrobenzyl            2-(2-tritylaminothiazol-4-yl)-2-(Z)-hydroxyiminoacetate with t-buyl           4-bromobut-2-enoate and hydrogenolysis of the resulting ester to              give 2-(2-tritylaminothiazol-4-yl)-2-[(Z)-3-t-butoxycarbonyl-                 prop-2-enyloxyimino]acetic acid. N.m.r. in solvent C: 1.44(s, 9H),            4.75(d, 2H), 5.92(m, 1H), 6.56(s, 1H), 6.7-6.9(m, 2H), 7.29(s, 15H).          2. N.m.r. in solvent C: 3.4(m, 2H), 3.9(d, 1H), 4.45(d, 1H), 4.9(m,           2H), 5.02(d, 1H), 5.7(m, 1H), 5.95(d, 1H), 6.83(s, 1H), 6.9(d, 1H),           7.32(s, 15H).                                                                 3. The starting material was prepared by reaction of ethyl                    2-(2-tritylaminothiazol-4-yl)-2-((Z)-2-bromoethoxyimino)acetate               (UK Patent Application 217702A) with the sodium salt of methyl                mercaptan and hydrolysis of the resulting ester to give 2-(2-trityl-          aminothiazol-4-yl)-2-((Z)-2-methylthioethoxyimino)acetic acid. N.m.r.         in solvent C: 2.1(s, 8H), 2.8(t, 2H) 4.3(t, 2H), 6.6(s, 1H), 7.3(s,           15H).                                                                         4. N.m.r. in solvent C: 2.1(s, 3H), 2.9(m, 2H), 3.5(s, 2H),                   3.95-4.6(m, 4H), 5.1(d, 1H), 5.95(d, 1H), 6.8(s, 1H), 7.35(s, 15H).           5. The starting material was prepared by oxidation of the product in          Footnote 3 to give 2-(2-tritylaminothiazol-4-yl)-2-((Z)-2-                    methanesulphonylethoxyimino)acetic acid.                                      N.m.r. in solvent C: 2.9(s, 3H), 3.5(t, 2H),4.5(t, 2H), 6.65(s, 1H),          7.3(s, 15H).                                                                  6. N.m.r. in solvent C: 3.0(s, 3H, 3.5-3.7(m, 4H), 4.3(m, 2H), 4.7(m,         2H),                                                                          5.1(d, 1H), 5.9(d, 1H) 6.8(s, 1H), 7.4(s, 15H).                               7. N.m.r. in solvent A: 3.4(s, 2H), 3.9(d, 1H), 4.4(d, 1H), 4.8(s, 2H),       4.9(d, 1H), 5.7(d, 1H), 6.8(s, 1H), 7.2(s, 15H).                              8. The starting material may be prepared as follows. Reaction of ethyl        2-(2-tritylaminothiazol-4-yl)-2-[(Z)-2-hydroxyethoxyimino]acetate with        diethylamino sulphur trifluoride and hydrolysis of the resulting ester        gave 2-(2-tritylaminothiazol-4-yl)-2-[(Z)-2-fluoroethoxyimino]acetic          acid.                                                                         N.m.r. in solvent A: 4.15(m, 1H), 4.38(m, 1H), 4.48(m, 1H), 4.92(m, 1H),      6.94(s, 1H), 7.4(s, 15H).                                                     9. N.m.r. in solvent C: 3.4(m, 2H), 4.2-4.6(m, 4H), 4.7(m, 1H), 5.0(m,        1H), 5.1(d, 1H), 5.9(d, 1H), 6.9(s, 1H), 7.4(s, 15H).                         10. The starting material was prepared by reaction of 2-bromo                 methylimidazole with N-hydroxy-phthalimide, deprotection to give              0-(imidazol-2-yl)methylhydroxylamine and condensation with                    2-(2-aminothiazol-4-yl)-glyoxylic acid to give 2-(2-aminothiazol-4-           yl)-2-[(Z)-(imidazol-2-yl)-methyoxyimino]acetic acid. N.m.r. in               solvent B: 5.42(s, 2H), 7.17(s, 1H), 7.67(s, 2H).                             11. A suspension of the product from Footnote 10 (4.4 mM) in DMF              (40 ul.) at 0° C. was dissolved by the addition of 3M HCl in           ether                                                                         (8.8 mM). N-hydroxybenzotriazole (4.4 mM) and t-butyl 7-amino-3-              azidomethylceph-3-em-4-carboxylate (4.0 mM) were added to the                 solution, followed by dropwise addition of a solution of DCCI                 (4,4 mM) in CH.sub.3 CN (15 ml.) during 20 minutes. The mixture was           left to stir for 23 hours at 0° C. and 1 hour at room                  temperature.                                                                  The precipitate was filtered, washed with DMF (3 ml.) and the                 residue evaporated to dryness. Trituration at 0° C. with aqueous       NaHCO.sub.3 (5%) yielded a yellow solid which was treated at room             temperature with TFA/H.sub.2 O (15:1) during 2 hours. Evaporation to          dyrness and purification of the residue by chromatography on                  Dianion HP 20 resin gave the required product.                                12. N.m.r. in solvent B: 3.6(m, 2H), 4.2(dd, 2H), 5.25(d, 1H), 5.5(s,         2H), 5.9(d, 1H), 7.25(s, 1H) 7.7(s, 2H).                                      13. This molecule is not tritylated on the                                    14. The starting material was prepared by condensation of                     0-(2,2,2-trifluoroethyl)hydroxylamine with 2-(2-aminothiazol-4-yl)-           glyoxylic acid to give 2-(2-aminothiazol-4-yl)-2-[(Z)-2,2,2-trifluoro-        ethoxyimino]acetic acid. N.m.r. in solvent B: 4.73(q, 2H), 6.93(s,            1H).                                                                          15. The method of condensation was that described in Footnote 11.             16. N.m.r. in solvent B: 3.5(d, 1H), 3.75(d, 1H), 3.95(d, 1H),                4.5(d, 1H), 4.75(d, 1H), 4.95(d, 1H), 5.3(d, 1H), 5.9(d, 1H), 7.2(s,          1H).                                                                          17. The starting material was prepared by reaction of                         0-(1-methylimidazol-2-yl)methylhydroxylamine with 2-(2-amino-                 thiazol-4-yl)glyoxylic acid to give 2-(2-aminothiazol-4-yl)-2-                [(Z)-(1-methylimidazol-2-yl)methoxy-imino]acetic acid.                        N.m.r. in solvent B: 3.90(s, 3H), 5.51(s, 2H), 7.17(s, 1H),                   7.57(s, 1H), 7.62(s, 1H).                                                     18. N.m.r. in solvent B: 3.6(m, 2H), 3.9(s, 3H), 4.2(dd, 2H), 5.2(d,          1H), 5.5(s, 2H), 5.85(d, 1H), 7.05(s, 1H), 7.7(dd, 2H).                   

Using the general process of reduction described in Footnote 3 of thedescription of starting materials for Example 16, the followingcompounds were prepared:

    ______________________________________                                         ##STR75##                                                                    R                  Footnotes                                                  ______________________________________                                        CH.sub.2 CCHCO.sub.2 H                                                                           1                                                          CH.sub.2 CH.sub.2 SCH.sub.3                                                                      2                                                          CH.sub.2 CH.sub.2 SO.sub.2 CH.sub.3                                                              3                                                          CH.sub.2 CN        4                                                          CH.sub.2 CH.sub.2 F                                                                              5                                                           ##STR76##         6                                                          CH.sub.2 CF.sub.3  7                                                           ##STR77##         8                                                          ______________________________________                                        1. N.m.r. in solvent B: 3.66(s, 2H), 3.78(m, 2H) 4.88(m, 2H),                 5.18(d, 1H), 5.88(d, 1H), 6.05(d, 1H), 6.92(d, 1H), 6.94(s, 1H).              2. N.m.r. in solvent B: 2.1(s, 3H), 2.85(t, 2H), 3.6-3.9(m, 4H),              4.4(t, 2H), 5.2(d, 1H), 5.9(d, 1H), 7.1(s, 1H).                               3. N.m.r. in solvent B: 2.95(s, 3H), 3.65(m, 6H), 4.6(t, 2H), 5.15(d,         1H), 5.85(d, 1H), 7.05(s, 1H).                                                4. N.m.r. in solvent A: 3.66(s, 2H), 3.78(q, 2H), 5.02(s, 2H),                5.15(d, 1H), 5.84(d, 1H) 6.98(s, 1H).                                         5. N.m.r. in solvent B: 3.6-4.0(m, 4H), 4.32(m, 1H), 4.4-4.7(m, 2H),          5.08(m, 1H), 5.24(d, 1H) 5.58(d, 1H), 6.98(s, 1H).                            6. N.m.r. in solvent B: 3.8(m, 4H), 5.15(d, 1H), 5.43(s, 2H), 5.86(d,         1H), 7.12, (s, 1H), 7.66(s, 2H).                                              7. N.m.r. in solvent B: 3.4-4.0(m, 4H), 4.65(d, 1H), 4.85(d, 1H),             5.17(d, 1H), 5.85(d, 1H), 7.05(s, 1H).                                        8. N.m.r. in solvent B: 3.6-3.9(m, 4H), 3.9(s, 3H); 5.15(d, 1H),              5.5(s, 2H), 5.85(d, 1H), 7.05(s, 1H), 7.65(dd, 2H).                       

EXAMPLES 54-75

The appropriate C3¹ -N-substituted CAZAMCA (1 eq.) and an excess (1.5eq.) of an appropriate quaternay heterocyclic salt were reacted in amixture of DMF/H₂ O (2:1) in the presence of NaHCO₃ (4 eq.) at 40° C.for 2.5 hr., and the product was purified by HPLC, using MeOH/H₂ O/HOAcas eluant, to give the following compounds:

    __________________________________________________________________________     ##STR78##                                                                                                    Yield                                         Example                                                                            R          R.sup.1         (%) Footnotes                                 __________________________________________________________________________    54   PhCH.sub.2                                                                                ##STR79##      30  1, 2                                      55   Et                                                                                        ##STR80##      58  3, 4                                      56.  furfuryl                                                                                  ##STR81##      40  5, 6                                      57.  CH.sub.2.CO.sub.2 H                                                                       ##STR82##      31  7, 8                                      58.  (CH.sub.2).sub.2 OH                                                                       ##STR83##      14  9, 10                                     59.  Et                                                                                        ##STR84##      33  11                                        60.  Et                                                                                        ##STR85##      11  12                                        61.  Et                                                                                        ##STR86##      47  13                                              ##STR87##                                                                                ##STR88##      10  14, 15                                    63.  (CH.sub.2).sub.2 OCH.sub.3                                                                ##STR89##      36  16, 17                                    64.  Et                                                                                        ##STR90##      10  18                                        65.  i-Pr                                                                                      ##STR91##       5  19, 20                                    66.  Et                                                                                        ##STR92##      23  21                                        67.  (CH.sub.2).sub.2 NH.sub.2                                                                 ##STR93##      30  22, 23                                    68.  (CH.sub.2).sub.2 F                                                                        ##STR94##      23  24, 25                                    69.  Et                                                                                        ##STR95##      15  26                                        70.  Me                                                                                        ##STR96##      22  27, 28                                    71.  Et                                                                                        ##STR97##      14  29                                        72.  allyl                                                                                     ##STR98##      13  30, 31                                    73.  Pr                                                                                        ##STR99##      18  32                                        74.  (CH.sub.2).sub.2 CN                                                                       ##STR100##     33  33, 34                                    75.  (CH.sub.2).sub.2 NH.CHO                                                                   ##STR101##     37  35                                        __________________________________________________________________________    Footnotes                                                                     1. Eluant proportion 35:65:1. N.m.r. in solvent B: 1.55(m, 6H),               3.4-3.6(m, 2H), 4.0(s,3H),                                                    4.7-5.0(m, 4H), 5.2(d, 1H), 5.9(d, 1H), 7.1(s, 1H), 7.2-7.5(m, 7H),           8.4(d, 2H).                                                                   2. The precursor C3.sup.1 N-benzyl CAZAMCA was obtained by reductive          amination of                                                                  benzaldehyde with CAZAMCA. Thus, CAZAMCA (1 eq.) was treated with             benzaldehyde (1.4 eq) and Et.sub.3 N (1.4 eq.) in anhydrous MeOH in the       presence of 3A                                                                molecular seives with NaBH.sub.3.CN (1.4 eq.) for 1/2 hr. at room             temperature. The                                                              product was purified by HPLC, eluant proportion 30:70:1. N.m.r. in            solvent B: 1.5(s, 6H),                                                        3.5-3.7(m, 2H), 3.8-4.0(m, 2H), 4.0-4.3(m, 2H), 5.2(d, 1H), 5.9(d, 1H),       7.0(s,                                                                        1H), 7.4-7.6(m, 5H).                                                          3. Used 2 eq. pyridinium salt. Reaction time 1.5 hr. Eluent proportion        25:75:1. N.m.r. in                                                            solvent B: 1.6(s, 6H), 3.2-3.8(m, 4H), 4.0(s, 3H), 4.6-4.8(m, 2H), 5.3(d,     1H), 6.0(d, 1H),                                                              7.15(s, 1H), 7.2-7.4(m, 2H), 8.2-8.4(m, 2H).                                  4. The precursor C.sub.3 ' N-ethyl CAZAMCA was obtained by reductive          amination of                                                                  acetaldehyde (1.1 eq.) with CAZAMCA (1.0 eq.) in presence of NaBH.sub.3       CN (1.0 eq.) and                                                              Et.sub.3 N (1.0 eq.). The acetaldehyde was added dropwise at room             temperature in MeOH, and                                                      the mixture stirred for 1/2 hr. The product was purified by preparative       HPLC using                                                                    MeOH/H.sub.2 O/HOAc 10:90:1 v/v/v, followed by 15:85:1. N.m.r. in solvent     B: 1.3 (t, 3H):                                                               1.6(s, 6H), 2.8-3.2(m, 2H), (m, 2H) 3.7-4.1(m, 4H), 5.3(d, 1H), 6.0(d,        1H), 7.2(s, 1H).                                                              5. N.m.r. in solvent B: 1.55(m, 6H), 3.3-3.6(m, 2H), 4.0(s, 3H),              4.8-5.0(m, 4H), 5.2(d, 1H),                                                   5.95(d, 1H), 6.4-6.6(m, 2H), 7.1(s, 1H) 7.3-7.6(d, 2H), 7.6- 7.7(m, 1H)       8.3-8.6(d, 2H).                                                               6. The precursor was obtained by reductive amination of 2-furaldehyde         with CAZAMCA,                                                                 as in Footnote 2. Reaction time 1.5 hr. Eluant proportion 20:80:1. N.m.r.     in solvent B:                                                                 1.6(s, 6H), 3.6-3.8(m, 2H), 3.9-4.1(m, 2H), 4.2-4.4(m, 2H), 5.25(d, 1H),      5.95(d,                                                                       1H), 6.5-6.8(m, 2H), 7.1(s, 1H), 7.8(d, 1H).                                  7. Eluant proportion 30:70:1. N.m.r. in solvent B: 1.5-1.6(m, 6h),            3.3-3.6(m, 2H),                                                               4.0(s, 3H), 4.4-4.6(m, 2H), 4.6-4.8(m, 2H), 5.3(d, 1H), 6.0(d, 1H),           7.1(s, 1H),                                                                   7.0-7.5(m, 2H), 8.3-8.5(m, 2H).                                               8. Precursor obtained as in Footnote 4, starting from glyoxylic acid.         Eluant proportion                                                             15:85:1. Yield 40% N.m.r. in solvent B; 1.6(m, 6H), 3.6-4.2(m, 6H),           5.3(d, 1H),                                                                   6.0(d, 1H), 7.1(s, 1H).                                                       9. Eluant proportion 20:80:1. N.m.r. in solvent B: 1.55(s, 6H),               3.2-3.6(m, 2H),                                                               3.5-3.8(m, 4H), 3.35(s, 3H), 4.6-4.8(m, 2H), 5.2(d, 1H), 5.9(d, 1H),          7.1(s, 1H),                                                                   7.3(d, 2H), 8.3(d, 2H).                                                       10. Precursor obtained by reductive amination of glycolaldehyde as in         Footnote 4. Eluant                                                            proportion 15:85:1. Yield 43%. N.m.r. in solvent B; 1.6(s, 6H),               3.0-3.4(m, 2H),                                                               3.6-4.0(m, 4H), 4.2-4.6(m, 2H), 5.2(d, 1H), 5.9(d, 1H), 7.0(s, 1H).           11. Reacted at 50° C. for 2 hrs. Eluant proportion 30:70:1. N.m.r.     in solvent B: 1.2(m,                                                          3H), 1.5(s, 6H), 3.2-3.8(m, 4H), 4.6-4.8(m, 2H), 5.2(s, 1H), 5.9(s, 1H),      7.1(s, 1H),                                                                   7.2-8.0(m, 7H).                                                               12. Reacted at 45° C. for 20 hrs. Eluant proportion 25:75:1. N.m.r     in solvent B:                                                                 1.0-1.3(m, 3H), 1.55(s, 6H), 3.5-3.8(m, 4H), 3.8(s, 3H), 4.3(d, 1H),          4.7(d, 1H),                                                                   5.2(d, 1H), 5.8(d, 1H), 7.05(s, 1H), 7.35(d, 1H), 7.7(d, 1H).                 13. Reacted at room temperature for 3.5 hrs, using N-(Boc-aminoethyl)-4-ch    loropyridinium                                                                chloride as the quaternary heterocyclic salt. The product was deprotected     by treating with                                                              TFA at room temperature for 1 hr. Eluant proportion 35:65:1. N.m.r. in        solvent B:                                                                    1.0-1.3(m, 3H), 1.6(s, 6H), 3.2-3.8(m, 4H), 4.3-4.8(m, 4H), 5.2(d, 1H)        5.9(d, 1H),                                                                   7.1(s, 1H), 7.2-7.4(d, 2H), 8.3-8.5(d, 2H).                                   14. Reacted at room temperature for 5 hrs. Eluant proportion 15:85:1.         N.m.r. in solvent B:                                                          1.6(s, 6H), 3.2-3.7(m, 2H) 4.0(s, 3H), 4.5-4.9(m, 2H), 5.0-5.4(m, 2H),        5.2(d, 1H),                                                                   5.9(d, 1H), 7.1(s, 1H), 7.2-7.4(m, 2H), 7.9-8.0(m, 2H), 8.2-8.5(m, 2H),       8.9-9.0(m, 2H).                                                               15. The precursor obtained as in Footnote 4 by reductive amination of         pyridine-4-                                                                   carboxaldehyde. Eluant proportion 20:80:1. Yield 37%. N.m.r. spectrum in      solvent B:                                                                    1.6(s, 6H), 3.6-3.8(m, 2H), 3.9-4.3(m, 2H), 4.4-5.0(m, 2H), 5.2(d, 1H),       6.0(d, 1H),                                                                   7.1(s, 1H), 8.0-8.3(m, 2H), 8.8-9.2(m, 2H).                                   16. Reacted at room temperature for 1.5 hrs. Eluant porportion 25:75:1.       N.m.r. in solvent                                                             B: 1.55(s, 6H), 3.2(s, 3H), 3.2-4.0(m, 6H), 3.9(s, 3H), 4.6-4.9(m,            2H), 5.2(d, 1H), 5.9(d, 1H), 7.1(s, 1H), 7.2(d, 2H), 8.2(d, 2H).              17. The precursor was obtained as in Footnote 4 by reductive amination of     2-methoxy-                                                                    acetaldehyde, 2 hrs at room temperature. Eluant proportion 20:80:1. Yield     24%. N.m.r. in                                                                solvent B: 1.6(s, 6H), 3.3(s, 3H), 3.2-4.0(m, 8H), 5.2(d, 1H), 5.9(d,         1H), 7.05(s, 1H).                                                             18. Reacted for 2 hrs. Eluant proportion 25:75:1. N.m.r. in solvent B:        1.2(t, 3H),                                                                   1.55(s, 6H), 2.3(s, 3H), 3.2-3.9(m 4H), 4.7(s, 2H), 4.9(m, 2H),               5.2-5.5(m, 3H),                                                               5.9-6.5(m, 2H), 7.0-7.5(m, 5H), 7.55(d, 2H), 8.4(d, 2H).                      19. Reaction time 8 hrs. at 45° C. Eluant proportion 20:80:1.          N.m.r. in solvent B:                                                          1.1-1.4(m, 6H), 1.6(s, 6H), 2.2-2.4(m, 1H), 3.2-3.6(m, 2H), 4.0(s, 3H),       4.2-4.8(m, 2H), 5.2(d, 1H), 5.9(d, 1H), 7.1(s, 1H), 7.3(d, 2H), 8.3(d,        2H).                                                                          20. The precursor was obtained as in Footnote 4, by reductive amination       of acetone                                                                    (4 eq.). Eluant proportion 20:80:1. Yield 50%. N.m.r. in solvent B:           1.2(d, 6H), 1.6(s, 6H),                                                       3.2-4.0(m, 5H), 5.2(d, 1H), 5.9(d, 1H), 7.05(d, 1H).                          21. Reacted at 40-45° C. for 4 hrs. Eluant proportion 25:75:1.         N.m.r. in solvent B: 1.2(t,                                                   3H), 1.55(s, 6H), 3.5(m, 2H), 3.4-3.8(m, 2H), 3.6(m, 2H), 5.2(d, 1H),         5.9(d, 1H), 5.9(s, 2H),                                                       7.05(s, 1H), 7.1-7.3(m, 1H), 8.5(d, 1H), 9.3(s, 1H).                          22. Reacted at room temperature for 1.5 hrs, using Boc-aminoethyl CAZAMCA     as                                                                            starting material. Eluant proportion 35:65:1. The product was deprotected     by solution in                                                                TFA at room temperature for 1/2 hr. N.m.r. in solvent B: 155(s, 6H),          2.6-4.0(m, 6H),                                                               4.0(s, 3H, 4.6-4.9(m, 2H), 5.3(d, 1H), 6.0(d, 1H), 7.0(s, 1H), 7.2(d,         1H), 8.2(d, 1H).                                                              23. The precursor was obtained by reductive amination of                      2-(Boc-amino)acetaldehyde at                                                  room temperature for 2 hrs. Eluant proportion 35:65:1. Yield 20%. N.m.r.      in solvent B:                                                                 1.4(s, 9H), 1.55(s, 6H), 2.7-3.4(m, 4H), 3.6-4.2(m, 4H), 5.2(d, 1H),          5.9(d, 1H),                                                                   7.05(s, 1H). The 2-(Boc-amino)propionaldehyde was obtained by oxidation       of                                                                            2-(Boc-amino)ethanol with pyridinium chlorochromate in CH.sub.2 Cl.sub.2      containing                                                                    sodium acetate, at 0° C. for 2 hrs, and purification by                chromatography on silica. Yield 68%.                                          24. Reaction time 2 hrs. at room temperature. Eluant proportion 25:75:1.      N.m.r. in solvent B:                                                          1.55(s, 6H), 3.2-3.6(m, 2H), 3.8-4.0(m, 2H), 4.0(s, 3H), 4.2-4.5(m, 1H),      4.8-5.1(m, 1H),                                                               4.6-4.8(m, 2H), 5.2(d, 1H), 5.9(d, 1H), 7.05(s, 1H), 7.3(d, 1H), 8.3(d,       1H).                                                                          25. The precursor was obtained by reductive alkylation of an excess of        2-fluoroacetaldehyde in                                                       CH.sub.2 Cl.sub.2 solution, for 2.5 hrs. at room temperature. Eluant          proportion 25:75:1. Yield 23%.                                                N.m.r. in solvent B: 1.55(s, 6H), 3.4-3.6(m, 2H), 3.6-4.1(m, 2H),             4.4-4.6(m, 1H),                                                               5.0-5.2(m, 1H), 5.2(d, 1H), 5.9(d, 1H), 7.1(s, 1H).                           26. Reaction carried out for 3 hrs. at room temperature and 1 hr. at          40° C. Eluant                                                          proportion 25:75:1. N.m.r. in solvent B: 1.2(m, 3H), 1.55(s, 6H),             3.5-3.9(m, 4H),                                                               3.95(s, 3H), 4.7(s, 2H), 5.25(d, 1H), 5.9(d, 1H), 7.0(s, 1H), 7.3-7.7(m,      1H), 8.2(d, 1H),                                                              8.65(d, 1H).                                                                  27. Reaction carried out at 45° C. for 1 hr. Eluant proportion         20:80:1.                                                                      N.m.r. in solvent B: 1.5(s, 6H), 3.1(s, 3H), 3.2(d, 1H), 3.5(d, 1H),          3.9(s, 3H), 4.5(d, 1H),                                                       4.65(d, 1H), 5.2(d, 1H), 5.85(d, 1H), 7.05(s, 1H), 7.0-7.2(m, 2H),            8.2-8.4(m, 2H).                                                               28. The CAZAMCA starting material was obtained as follows: A solution of      4-chloro-                                                                     N-methylbutyramide in CH.sub.2 Cl.sub.2 was treated dropwise with silver      fluoroborate in                                                               a mixture of CH.sub.2 Cl.sub.2 and benzene at -20° C., and the         reaction was allowed                                                          to warm to room temperature. The silver chloride precipitate was filtered     off, and the                                                                  product was purified by silica chromatography, eluting with CH.sub.2          Cl.sub.2 /MeOH, 4:1,                                                          to yield N-methyliminobutyrolactone fluoroborate, 71%, which was              converted to free base                                                        by reaction with 1 eq. of 1,8-diazabicylo[5,4,0]undec-7-ene (DBU) in          CH.sub.2 Cl.sub.2                                                             (yield 62% of free base). This product was reacted with                       7-[2-(2-aminothiazol-4-yl)-2-                                                 [(Z)-1-carboxy-1-methylethoxyimino]acetamido]-3-iodomethylceph-3-em-4-carb    oxylic                                                                        acid in acetonitrile at room temperature for 1/2 hr. to give the              corresponding                                                                 3-[N-(1,2,3,4-tetrahydo-2-furylidene)-N-methylaminomethyl]cephem, which       was                                                                           hydrolysed with 4 eq. of sodium bicarbonate in water at room temperature      for 1/2 hr.,                                                                  and the product purified by preparative HPLC eluting with MeOH/H.sub.2        O/HOAc, 20:80:1 to                                                            yield the required starting material, yield 45%.                              29. Reaction carried out in DMF/H.sub.2 O, 1:1, at 40° C. for 4        hours. Eluant proportion                                                      25:75:1. N.m.r. in solvent B: 1.1(m, 3H), 1.55(s, 6H), 2.5(s, 3H),            3.0-3.7(m, 4H),                                                               3.8(s, 3H), 4.6(s, 2H), 5.2(d, 1H), 5.9(d, 1H), 7.0-7.05(m, 3H), 8.2(d,       1H).                                                                          30. Reaction at room temperature for 1.5 hrs. Eluant proportion 25:75:1.      N.m.r. in                                                                     solvent B: 1.6(s, 6H), 3.2-3.6(m, 4H), 4.0(s, 3H), 4.0-4.3(m, 1H),            4.5-4.8(m, 2H),                                                               5.0-5.2(m, 1H), 5.2(d, 1H), 5.5-6.0(m, 1H), 5.9(d, 1H), 7.1(s, 2H),           7.2(d, 2H), 8.3(d, 1H).                                                       31. The precursor CAZAMCA derivative was a mixture of N-allyl and             N-propyl,                                                                     obtained by reductive alkylation of acrylaldehyde, as in Footnote 4,          using 1.2 eq.                                                                 of the aldehyde, and reacting at room temperature for 1 hr. Eluant            proportion                                                                    20:80:1. This mixture was used to prepare the final product, purification     of which                                                                      separated the N-allyl and N-propyl analogues.                                 32. Eluant proportion 25:75:1. N.m.r. in solvent B: 0.9(t, 3H), 1.6(s,        6H), 3.1-3.8(m, 4H),                                                          3.9(s, 3H), 4.5-4.8(m, 2H), 5.2(d, 1H), 5.9(d, 1H), 7.0(s, 1H), 7.2(d,        2H), 8.2(d, 2H).                                                              33. Reacted overnight at room temperature. Eluant proportion 20:80:1.         N.m.r. in solvent                                                             B: 1.5(s, 6H), 2.6-3.0(m, 2H), 3.95(d, 1H), 3.25(d, 1H), 3.95(s, 3H),         4.5-4.8(m, 2H),                                                               5.2(d, 1H), 5.9(d, 1H), 7.0(s, 1H), 7.4(d, 2H), 8.4(d, 2H).                   34. The precursor was obtained as in Footnote 4 by Michael addition of        acrylonitrile to                                                              CAZAMCA The product was purified by HPLC, eluant proportion 15:85:1.          Yield 31%.                                                                    N.m.r. in solvent B: 1.55(s, 6H), 2.8-3.1(m, 2H), 3.2-3.4(m, 2H),             3.5-3.8(m, 2H), 3.8-4.2(m, 2H), 5.2(d, 1H), 5.9(d, 1H), 7.0(s, 1H).           35. This compound obtained by reacting the product of Example 67 with         formic acetic                                                                 anhydride in MeOH at room temperature for 1/2 hr. Eluant proportion           20:80:1. N.m.r.                                                               in solvent B: 1.55(s, 6H), 3.2-3.8(m, 6H), 3.9(s, 3H), 3.5-3.8(m, 2H),        5.2(d, 1H),                                                                   5.9(d, 1H), 7.0(s, 1H), 7.2(d, 2H), 8.0(s, 1H), 8.2(d, 2H).               

EXAMPLES 76-87

The appropriate3-acetoxymethyl-7-[2-(2-aminothiazol-4-yl)-2-(substituted oximino)acetamido]ceph- 3-em-4-carboxylic acid and the appropriateamino-substituted quaternary heterocycle were reacted together at 85° C.at pH 7.0-7.5. The pH was maintained with this range by the addition ofdilute HOAc or NaHCO₃ solution as necessary. The product was purified bypreparative HPLC, using a mixture of MeOH/H₂ O/HOAc as eluant.

The following compounds were prepared:

    __________________________________________________________________________     ##STR102##                                                                   Example                                                                            R.sup.11 R      R.sup.1         Yield                                                                             Footnotes                            __________________________________________________________________________    76.  Me       H                                                                                     ##STR103##     11  1                                    77.  Me       H                                                                                     ##STR104##     6   2                                    78   C(CH.sub.3).sub.2 COOH                                                                 H                                                                                     ##STR105##     8   3                                    79   Me       H                                                                                     ##STR106##     7   4, 5                                 80   Me       Me                                                                                    ##STR107##     31  6, 7                                 81.  C(CH.sub.3).sub.2 COOH                                                                 H                                                                                     ##STR108##     6   8                                    82.  C(CH.sub.3).sub.2 COOH                                                                 H                                                                                     ##STR109##     9   9                                    83.  C(CH.sub.3).sub.2 COOH                                                                 Me                                                                                    ##STR110##     13  10                                   84.  C(CH.sub.3).sub.2 COOH                                                                 Et                                                                                    ##STR111##     13  11, 12                               85.  C(CH.sub.3).sub.2 COOH                                                                 (CH.sub.2).sub.2 NH.sub.2                                                             ##STR112##     7   13, 14, 15                           86.  C(CH.sub.3).sub.2 COOH                                                                 Et                                                                                    ##STR113##     4   16, 17                               87.  C(CH.sub.3).sub.2 COOH                                                                 H                                                                                     ##STR114##     12  18                                   __________________________________________________________________________    Footnotes                                                                     1. Reaction time 3 hrs. Eluant proportion 15-20: 85-80:1. N.m.r. in           solvent B: 3.55(s, 2H), 3.95(s, 3H),                                          4.4(s, 3H), 4.4(s, 2H), 5.2(d, 1H), 5.8(d, 1H), 7.05(s, 1H), 7.25(d, 1H),     7.6(d, 1H), 7.85(t, 1H),                                                      8.6(d, 1H), 8.8(d, 1H), 9.8(s, 1H).                                           2. Reaction time 2 hrs. Eluant proportions as in Footnote 1. N.m.r. in        solvent B; 3.55(s, 2H),                                                       4.0(s, 3H), 4.46(s, 3H), 4.46(s, 2H), 5.15(d, 1H), 5.75(d, 1H), 7.0(s,        1H), 7.0(d, 1H), 7.45(d, 1H),                                                 7.8-8.05(m, 2H), 9.3(d, 1H), 9.5(d, 1H).                                      3. Reaction time 2 hrs. Eluant proportion 30-35: 70-65:1. N.m.r. in           solvent B: 1.55(s, 6H), 3.55(s, 2H),                                          4.4(s, 3H), 4.4(s, 2H), 5.15(d, 1H), 5.8(d, 1H), 7.05(s, 1H), 7.15(d,         1H), 7.55(d, 1H), 7.75(t, 1H),                                                8.5(d, 1H), 8.7(d, 1H), 9.7(s, 1H).                                           4. Eluant proportion 20-25: 80-75:1. N.m.r. in solvent B: 3.55(s, 2H),        3.95(s, 3H), 4.4(s, 2H),                                                      5.2(d, 1H), 5.5(s, 2H), 5.8(d, 1H), 7.05(s, 1H), 7.3(d, 1H), 7.65(d, 1H),     7.85(t, 1H), 8.6(d, 1H),                                                      8.8(d, 1H), 9.8(s, 1H).                                                       5. The 5-amino-2-carbamoylmethylisoquinolinium chloride used as starting      material was obtained by                                                      alkylation of 5-aminoisoquinoline (1 eq.) with 2-chloroacetamide (1 eq.)      in DMF overnight at 45° C.                                             The precipitate was washed with DMF, then CH.sub.2 Cl.sub.2, and dried.       Yield 76%. N.m.r. in solvent B:                                               5.45(s, 2H), 7.4(dd, 1H), 7.6(d, 1H), 7.75(t, 1H), 8.45(d, 1H), 8.6(d,        1H), 9.8(s, 1H).                                                              6. Eluant proportion as in Footnote 4. N.m.r. in solvent B: 2.8(s, 3H),       3.6(s, 2H), 4.0(s, 3H),                                                       4.15(s, 2H), 4.45(s, 3H), 5.15(d, 1H), 5.75(d, 1H), 7.0(s, 1H), 7.6-8.1,      8.4-8.6 and                                                                   9.6-9.9(3m, 6H).                                                              7. The 2-methyl-5-methylaminoisoquinolinium iodide used as starting           material was obtained by                                                      reacting 5-methylaminoisiquinoline with a large excess of methyl iodide       at room temperature for 17                                                    hrs. in CH.sub.2 Cl.sub.2. The solvents were evaporated to give the           required salt. Yield 100%.                                                    N.m.r. in solvent B: 4.0(s, 3H), 4.4(s, 3H), 7.05(d, 1H), 7.55(d, 1H),        7.85(t, 1H), 8.6(s, 2H),                                                      9.8(s, 1H).                                                                   8. Reaction time 3 hrs. Eluant proportion 25:75:1. N.m.r. in solvent B:       1.5(s, 6H), 3.55(s, 2H),                                                      4.45(s, 2H), 5.2(d, 1H), 5.45(s, 2H), 5.85(d, 1H), 7.05(s, 1H),               7.15-7.4(m, 1H), 7.5-7.9(m, 2H),                                              8.3-8.9(m, 2H), 9.7-9.9(m, 1H).                                               9. Eluant proportions 20-25-30:80-75-70:1. N.m.r. in solvent B; 1.5(s,        6H), 3.6(s, 2H),                                                              4.5(s, 5H), 5.2(d, 1H), 5.85(d, 1H), 7.0(s, 1H), 6.7-7.1(m, 1H), 7.5(d,       1H), 7.8-8.1(m, 2H),                                                          9.3-9.6(m, 2H).                                                               10. Eluant proportion 20-30:80-70:1. N.m.r. in solvent B: 1.5(s, 6H),         2.8(s, 3H), 3.55(s, 2H),                                                      4.4(s, 2H), 4.45(s, 3H), 5.1(d, 1H), 5.8(d, 1H), 7.05(s, 1H), 7.0-7.2,        7.6-8.2, 8.4-8.6, and                                                         9.6-10.0 (4 × m, 6H).                                                   11. Eluant proportion 25-30:75-70:1. N.m.r. in solvent B: 0.9(t, 3H),         1.55(s, 6H), 3.2(q, 2H),                                                      3.55(s, 2H), 4.4(s, 2H), 4.45(s, 3H), 5.05(d, 1H), 5.75(d, 1H), 7.0(s,        1H), 7.0-7.2, 7.6-8.2,                                                        8.4-8.6 and 9.6-10.0 (4 × m, 6H).                                       12. The 5-ethylamino-1-methylisoquinolinium iodide was prepared by the        process described in                                                          Footnote 7. N.m.r. in solvent B: 1.3(t, 3H), 3.3(q, 2H), 4.4(s, 3H),          7.1(d, 1H), 7.55(d, 1H),                                                      7.8(t, 1H), 8.6(d, 1H), 8.65(d, 1h), 9.75(s, 1H).                             13. The quaternary heterocycle used as starting material was                  5-(2-Boc-aminoethylamino)-2-                                                  methylisoquinolinium methosulphate. Reaction time 2.5 hrs. Eluant             proportion 30-40: 70-60:1.                                                    N.m.r. in solvent B: 1.3(s, 9H), 1.55(s, 6H), 3.1-3.5(m, 4H), 3.55(s,         2H), 4.4(s, 2H),                                                              4.45(s, 3H), 5.05(d, 1H), 5.75(d, 1H), 7.0(s, 1H), 7.0-7.2, 7.6-8.2,          8.4-8.6 and                                                                   9.6-10.0 (4 × m, 6H).                                                   14. The product was deprotected by dissolving in CH.sub.2 Cl.sub.2 /TFA       (1:2) for 10 minutes at                                                       room temperature. N.m.r. in solvent B: 1.55(s, 6H), 2.9-3.5(m, 4H),           3.55(s, 2H), 4.4(s, 2H),                                                      4.45(s, 3H), 5.05(d, 1H), 5.75(d, 1H), 7.0(s, 1H), 7.0-7.2, 7.6-8.2,          8.4-8.6 and                                                                   9.6-10.0 (4 × m, 6H).                                                   15. The 5-(2-Boc-aminoethylamino)-2-methylisoquinolinium methosulphate        starting material was                                                         prepared as follows: 5-Hydroxyisoquinoline (1 eg.) and ethylene diamine       (10 eq.), were reacted                                                        in a Bucherer reaction, in water with sodium hydrogen sulphite (2 eq.) at     160° C. for 20 hrs.                                                    The product was purified by chromatography on silica, eluting with            CH.sub.2 Cl.sub.2 /MeOH,                                                      97-90:3-10. Yield 26%. N.m.r. in d.sub.6 -DMSO: 2.9(t, 2H), 3.2(dt, 2H),      6.3(t, 1H),                                                                   6.75(dd, 1H), 7.25(d, 1H), 7.45(t, 1H), 8.05(d, 1H), 8.4(d, 1H), 9.15(s,      1H). The Boc derivative                                                       was formed by reacting the above product with 0,0.sup.1 -di-tert-butyl        carbonic anhydride                                                            (1.5 eq.) in THF for 1 hr. The Boc compound was purified by                   chromatography on silica, eluting                                             with ether. Yield 66%. N.m.r. in CDCl.sub.3 : 1.45(s, 9H), 3.2-3.7(m,         4H), 4.8-5.1(m, 1H),                                                          5.3-5.6(m, 1H), 6.7(dd, 1H), 7.3(d, 1H), 7.45(t, 1H), 7.65(d, 1H),            8.45(d, 1H), 9.15(s, 1H).                                                     This Boc product was quaternised with dimethyl sulphate, in CH.sub.2          Cl.sub.2 at room temperature                                                  or 2 hrs. The solvent was evaporated, and the residue was washed with         ether. N.m.r. in CDCl.sub.3 ;                                                 1.45(s, 9H), 3.2(m, 2H), 3.55(m, 2H), 3.8(s, 6H), 4.5(s, 3H), 6.7(d, 1H),     7.3(d, 1H), 7.55(t, 1H),                                                      8.1(d, 1H), 8.5(d, 1H), 9.5(s, 1H).                                           16. Eluant proportion as in Footnote 11. N.m.r. in solvent B: 0.95(t,         3H), 1.55(s, 6H), 3.25(q, 2H),                                                3.6(s, 2H), 4.4(s, 2H), 4.6(s, 3H), 5.05(d, 1H), 5.8(d, 1H), 7.0(s, 1H),      7.2-7.5, 7.8-8.2,                                                             9.2-9.5(3 × m, 6H).                                                     17. The 5-ethylamino-1-methylquinolinium iodide used as starting material     obtained by the                                                               process described in Footnote 7, starting from 5-ethylaminoquinoline, 72      hrs at room temperature.                                                      Yield 100%. N.m.r. in solvent B: 1.3(t, 3H), 3.35(q, 2H), 4.5(s, 3H),         6.85(d, 1H), 7.35(d, 1H),                                                     7.7-8.1(m, 2H), 9.25(d, 1H), 9.45(d, 1H).                                     18. Eluant proportion as in Footnote 10. N.m.r. in solvent B: 1.55(s,         6H), 3.55(s, 2H) 4.3(s, 2H),                                                  4.5(s, 3H), 5.2(d, 1H), 5.85(d, 1H), 7.0(s, 1H), 7.2(d, 1H), 7.6(dd, 1H),     7.8(dd, 1H), 8.15(d, 1H),                                                     8.6(d, 1H), 8.85(d, 1H).                                                  

EXAMPLES 88-106

The appropriate quaternary chloro-hetercycle (1 eq.) was reacted with3-aminomethyl7-[2-(2-aminothiazol-4-yl)-2-[(Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylicacid (1 eq.) in DMF/H₂ O (2:1). The solvents were evaporated and theresidue was purified by HPLC, eluting with a mixture of MeOH/H₂ O/HOAc.The following compounds were prepared:

    __________________________________________________________________________     ##STR115##                                                                   Example                                                                              R                   Yield                                                                             Footnotes                                      __________________________________________________________________________            ##STR116##         33  1, 2, 38                                               ##STR117##         23  3, 4, 38                                       90.                                                                                   ##STR118##         18  5, 6, 38                                               ##STR119##         26  7, 8, 38                                               ##STR120##         35  9, 10, 38                                              ##STR121##         40  11, 12, 38                                             ##STR122##         28  13, 14, 38                                             ##STR123##         40  15, 16, 38                                             ##STR124##         45  17, 18, 38                                             ##STR125##         44  19, 20, 38                                             ##STR126##         15  21, 22, 38                                             ##STR127##         14  23, 24, 38                                     100.                                                                                  ##STR128##         21  25, 26, 38                                     101.                                                                                  ##STR129##         36  27, 28, 38                                     102.                                                                                  ##STR130##         35  29, 30, 38                                     103.                                                                                  ##STR131##         37  31, 32, 38                                     104.                                                                                  ##STR132##         32  33, 34, 38                                     105.                                                                                  ##STR133##         17  35, 36, 38                                     106.                                                                                  ##STR134##         21  37, 38                                         __________________________________________________________________________    Footnotes                                                                     1. Reaction time 3 hrs. at room temperature. Eluant proportion 20:80:1.       N.m.r. in                                                                     solvent B: 1.55(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.35(s, 2H), 5.2(d, 1H),      5.3(s, 2H),                                                                   5.85(d, 1H), 7.05(s, 1H), 6.9-7.2 and 8.2-8.6 (2 × m, 4H).              2. The starting pyridinium salt was obtained by condensation of               4-methylthio-                                                                 pyridine and 4-chloromethyl-2-quanidinothiazole hydrochloride in              EtOH/DMF                                                                      (5:1) under reflux overnight. The product was purified by silica              chromatography,                                                               eluting with CH.sub.2 Cl.sub.2 /MeOH, 100-70:30. Yield 20%. N.m.r. in         solvent B: 2.65(s, 3H), 5.65(s, 2H), 7.55(s, 1H), 7.85 and 8.9 (2 ×     d, 4H).                                                                       3. Reaction time 1 hr. at room temperature. Eluant proportion as in           Footnote 1.                                                                   N.m.r. in solvent B: 1.55(s, 6H), 3.45(d, 1H), 3.75(d, 1H), 4.4(s, 2H),       5.1(s, 2H),                                                                   5.25(d, 1H), 5.9(d, 1H), 5.3(s, 1H), 7.1(s, 1H), 7.0-7.3(m, 2H),              8.1-8.5(m, 2H).                                                               4. The starting pyridinium salt was obtained by the process in Footnote       2, by                                                                         alkylating 4-methylsulphonylpyrimidine with 6-chloromethyluracil. Yield       47%.                                                                          N.m.r. in solvent B: 2.7(s, 3H), 5.4(s, 3H), 7.9(d, 2H), 8.7(d, 2H).          5. Reaction time 2.5 hrs. at room temperature. Eluant proportion 30:70:1.     N.m.r. in                                                                     solvent B: 1.55(s, 6H), 3.55(s, 2H), 4.4(s, 2H), 5.2(d, 1H), 5.9(d, 1H),      6.0(s, 2H),                                                                   6.9-7.2(m, 2H), 7.1(s, 1H), 7.95(s, 4H), 8.1-8.5(m, 2H).                      6. The starting pyridinium salt was obtained by the process of Footnote       2. Yield 30%.                                                                 N.m.r. in solvent B: 2.65(s, 3H), 6.25(s, 2H), 7.9(s, 4H), 7.9 and 8.7(2      × d, 4H).                                                               7. Reaction as Footnote 3. N.m.r. in solvent B: 1.6(s, 6H), 3.6(s, 2H),       4.4(s, 2H),                                                                   5.3(d, 1H), 5.4(s, 2H), 5.95(s, 1H), 7.1(s, 1H), 7.0-7.3(m, 2H),              8.2-8.6(m, 2H),                                                               8.85(s, 1H).                                                                  8. The starting pyridinium salt was obtained by the process of Footnote       2, carried                                                                    out at room temperature for 40 hrs. Yield 81%. N.m.r. in solvent B:           2.7(s, 3H),                                                                   5.65(s, 2H), 7.95(d, 2H), 8.8(d, 2H), 8.8(s, 1H).                             9. Reaction time 2 hrs. Eluant proportion 25:75:1. N.m.r. in solvent B:       1.55(s, 6H),                                                                  3.25(s, 3H), 3.45(s, 3H), 3.55(s, 2H), 4.35(s, 2H), 4.7(s, 4H), 5.25(d,       1H), 5.9(d, 1H),                                                              7.0(s, 1H), 6.8-7.2(m, 2H), 7.8(s, 1H), 7.9-8.3(m, 2H).                       10. The starting pyridinium salt was obtained by the process of Footnote      2. Yield                                                                      46%. N.m.r. in solvent B: 2.7(s, 3H), 3.2(s, 3H), 3.45(s, 3H), 4.85(s,        4H),                                                                          7.85(s, 1H), 7.95(d, 2H), 8.5(d, 2H).                                         11. Reaction time 1.5 hrs. at room temperature, using a 50% excess of         the                                                                           pyridinium salt. Eluant proportion 30:70:1. N.m.r. in solvent B: 1.55(s,      6H),                                                                          2.55(s, 3H), 3.4(d, 1H), 3.7(d, 1H), 4.35(s, 2H), 5.25(d, 1H), 5.9(d,         1H),                                                                          5.45(s, 2H), 7.05(s, 1H), 7.55(s, 1H), 6.9-7.2(m, 2H), 8.2-8.6(m, 2H).        12. The starting pyridinium salt was obtained by the process of Footnote      2, in EtOH                                                                    as solvent. Yield 19%. Nmr in solvent B: 2.6(s, 3H), 2.7(s, 3H), 5.75(s,      2H), 7.75(s,                                                                  1H), 7.95(d, 2H), 8.8(d, 2H).                                                 13. Reaction time 1.5 hrs. at room temperature. Eluant proportion             30:70:1. N.m.r. in                                                            solvent B: 1.3(t, 3H), 1.55(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.35(s, 2H),      4.4(q, 2H),                                                                   5.25(d, 1H), 5.9(d, 1H), 5.6(s, 2H), 7.15(s, 1H), 6.9-7.2(m, 2H), 8.25(s,     1H), 8.2-                                                                     8.6(m, 2H).                                                                   14. The starting pyridinium salt was obtained by the process of Footnote      2. Yield                                                                      70%. N.m.r. in solvent B: 1.3(t, 3H), 2.65(s, 3H), 4.35(q, 2H), 5.86(s,       2H), 7.9(d,                                                                   2H), 8.25(s, 1H), 8.8(d, 2H).                                                 15. Reaction time 2 hrs. at room temperature. Eluant proportion as            Footnote 1.                                                                   N.m.r. in solvent B: 1.55(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.35(s, 2H),        5.2(d, 1H),                                                                   5.5(s, 2H), 5.85(d, 1H), 7.1(s, 1H) 6.9-7.2(m, 2H), 8.05(s, 1H),              8.1-8.4(m, 2H).                                                               16. The starting pyridinium salt was obtained by the process of Footnote      2. Yield                                                                      18%. N.m.r. in solvent B: 2.75(s, 3H), 5.9(s, 2H), 7.8(d, 2H), 8.25(s,        1H), 8.85(d,                                                                  2H).                                                                          17. Reaction time 1/2 hr. at room temperature. Eluant proportion as           Footnote 5.                                                                   N.m.r. in solvent B: 1.55(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.25(d, 1H),        4.5(d, 1H),                                                                   5.2(d, 1H), 5.6(s, 2H), 5.9(d, 1H), 7.05(s, 1H), 7.0-7.2(m, 2H), 8.4(s,       1H), 8.2-                                                                     8.6(m, 2H).                                                                   18. The starting pyridinium salt is obtained by the process of Footnote       2. Yield 90%.                                                                 N.m.r. in solvent B: 2.7(s, 3H), 5.9(s, 2H), 8.05(d, 2H), 8.45(s, 1H),        8.8(d, 2H).                                                                   19. Reaction time 2 hrs. at room temperature. Eluant proportion as            Footnote 2.                                                                   N.m.r. in solvent B; 1.55(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.25(d, 1H),        4.5(d, 1H),                                                                   5.25(d, 1H), 5.9(d, 1H), 5.95(s, 2H), 7.15(s, 1H), 6.9-7.2(d, 2H),            8.3-8.7(d, 2H), 9.4(s,                                                        1H).                                                                          20. The starting pyridinium salt was obtained by the process of Footnote      2, but for                                                                    48 hrs. at room temperature. Yield 48%. N.m.r. in solvent B: 2.55(s, 3H),     2.7(s, 3H),                                                                   6.25(s, 2H), 7.95(d, 2H), 8.95(d, 2H), 9.45(s, 1H).                           21. Reaction time 3.5 hrs. at room temperature. Eluant proportion             20-30:80-70:1.                                                                N.m.r. in solvent B: 1.55(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.4(s, 2H),         5.25(d, 1H), 5.4(s,                                                           1H), 5.9(d, 1H), 7.15(s, 1H), 6.9-7.2(m, 2H), 7.35(s, 1H), 8.55(s, 1H),       8.2-8.6(m,                                                                    2H).                                                                          22. The starting pyridinium salt was obtained by the process of Footnote      2. Yield                                                                      39%. N.m.r. in solvent B: 2.7(s, 3H), 5.7(s, 2H), 7.4(s, 1H), 7.95(d,         2H), 8.5(s, 1H),                                                              8.8(d, 2H).                                                                   23. The 3-aminomethyl cephem was alkylated with the corresponding             2-(Boc-                                                                       amino)thiazole derivative, at room temperature for 40 minutes. The Boc        protecting                                                                    group was removed by dissolving the product in TFA/CH.sub.2 Cl.sub.2          (4:1) at room                                                                 temperature for 50 minutes. Eluant proportion 30-35:70-65:1. N.m.r. in        solvent B:                                                                    1.55(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.4(s, 2H), 5.2(s, 2H), 5.25(d, 1H),     5.9(d, 1H),                                                                   7.05(s, 1H), 6.9-7.2(m, 2H), 8.0-8.4(m, 2H).                                  24. The starting Boc-amino-chloromethylthiazole was obtained by the           process of                                                                    Footnote 2. Yield 65%. N.m.r. in solvent B; 1.45(s, 9H), 2.7(s, 3H),          5.7(s, 2H),                                                                   7.35(s, 1H), 7.9(d, 2H), 8.75(d, 2H).                                         25. Reaction time 1.25 hrs. at room temperature. Eluant proportion            30-40:70-60:1.                                                                N.m.r. in solvent B: 1.5(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.25(d, 1h),         4.5(d, 1H), 5.15(d,                                                           1H), 5.85(d, 1H), 6.0(s, 2H), 7.1(s, 1H), 7.0-7.2(m, 2H), 7.5-7.7(m, 2H),     7.7-7.9(m,                                                                    2H), 8.2-8.6(m, 2H).                                                          26. The starting pyridinium salt was obtained by the process of Footnote      2, at room                                                                    temperature overnight followed by 3 hrs. under reflux in EtOH/DMF (3:2).      The                                                                           solvent was evaporated, and the product was precipitated with ether.          Yield 54%.                                                                    N.m.r. in solvent B: 2.7(s, 2H), 6.35(s, 2H), 7.55(m, 2H), 7.75(m, 2H),       8.0(d, 2H),                                                                   8.9(d, 2H).                                                                   27. Reaction time 40 minutes at room temperature. Eluant proportion as        Footnote 1.                                                                   N.m.r. in solvent B: 1.55(s, 6H), 2.4(dt, 2H), 3.4(d, 1H), 3.7(d, 1H),        4.4(m, 4H),                                                                   5.2(d, 1H), 5.5(t, 1H), 5.9(d, 1H), 6.9(d, 1H), 7.1(s, 1H), 7.0-7.2(m,        2H), 7.15(t,                                                                  1H), 7.55(dt, 1H), 7.9(dd, 1H), 8.2-8.6(m, 2H).                               28. The starting pyridinium salt was obtained by the process of Footnote      2, at room                                                                    temperature overnight followed by 24 hrs. under reflux. Yield 20%. N.m.r.     in sol-                                                                       vent B: 2.5(dt, 2H), 2.7(s, 3H), 4.7(t, 2H), 5.5(t, 1H), 6.9(d, 1H),          7.15(t, 1H), 7.55(dt,                                                         1H), 7.9(dd, 1H), 8.0(d, 2H), 8.9(d, 2H).                                     29. Reaction time 2 hrs. at room temperature. Eluant proportion               10-25:90-75:1.                                                                N.m.r. in solvent B: 1.55(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 3.9(s, 3H),         4.4(s, 2H), 5.2(d,                                                            1H), 5.85(d, 1H), 5.85(s, 2H), 7.0(s, 1H), 7.7(d, 1H), 7.75(d, 1h),           7.0-7.4(m, 2H), 8.2-                                                          8.6(m, 2H).                                                                   30. The starting pyridinium salt was obtained by the process of Footnote      2, at room                                                                    temperature for 96 hrs. Yield 30%. N.m.r. in solvent B: 2.7(s, 3H),           3.95(s, 3H),                                                                  6.2(s, 2H), 7.7(d, 1H), 7.75(d, 1H), 7.95(d, 1H), 8.85(d, 1H).                31. Reaction time 3 hrs. room temperature. Eluant proportion                  10-20:90-80:1. N.m.r.                                                         in solvent B: 1.55(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.4(s, 2H), 5.2(d,         1H), 5.75(s, 2H),                                                             5.85(d, 1H), 7.05(s, 1H), 7.65(s, 2H), 7.0-7.3(m, 2H), 8.2-8.4(m, 2H).        32. The starting pyridinium salt was obtained by the process of Footnote      2. Yield                                                                      83%. N.m.r. in solvent B: 2.75(s, 3H), 6.15(s, 2H), 7.75(s, 2H), 8.05(d,      2H), 8.85(d,                                                                  2H).                                                                          33. Reaction time 1.5 hrs. at room temperature. Eluant proportion as          Footnote 1.                                                                   N.m.r. in solvent B: 1.5(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.4(s, 2H),          5.15(d, 1H), 5.55(s,                                                          2H), 5.85(d, 1H), 7.05(s, 1H), 7.05(dd, 1H), 7.0-7.2(m, 2H), 7.4(d, 1H),      7.55(d, 1H),                                                                  8.2-8.6(m, 2H).                                                               34. The starting pyridinium salt was obtained by the process of Footnote      2, at room                                                                    temperature overnight followed by 4 hrs. under reflux. Yield 46%. N.m.r.      in sol-                                                                       vent B: 2.65(s, 3H), 5.9(s, 2H), 7.05(dd, 1H), 7.4(d, 1H), 7.55(d, 1H),       7.85(d, 2H),                                                                  8.8(d, 2H).                                                                   35. Reaction time 3 hrs. at room temperature. Eluant proportion               40-50:60-50:1.                                                                N.m.r. in solvent B: 1.55(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.3(d, 1H),         4.5(d, 1H), 5.2(d,                                                            1H), 5.85(s, 2H), 5.9(d, 1H), 7.05(s, 1H), 7.0-7.3(m, 2H), 7.7(d, 1H),        8.1(dd, 1H),                                                                  8.5(d, 1H), 8.2-8.6(m, 2H).                                                   36. The starting pyridinium salt was obtained by the process of Footnote      2, heating                                                                    under reflux for 6 hrs., then overnight at room temperature. Yield 77%.       N.m.r. in                                                                     solvent B: 2.7(s, 3H), 6.1(s, 2H), 7.7(d, 1H), 7.95(d, 2H), 8.1(dd, 1H),      8.5(d, 1H),                                                                   8.85(d, 2H).                                                                  37. This compound obtained by reduction of the product of Example 105         with                                                                          titanium trichloride (5 eq.) in MeOH/TFA (99:1) for 1 hr. at room             temperature.                                                                  Eluant proportion as Footnote 1. N.m.r. in solvent B: 1.55(s, 6H), 3.4(d,     1H), 3.7(d,                                                                   1H), 4.3(d, 1H), 4.5(d, 1H), 5.2(d, 1H), 5.9(d, 1H), 5.9(s, 2H), 7.1(s,       1H), 7.0-7.3(m,                                                               2H), 7.44(d, 1H), 7.85(dd, 1H), 7.9(d, 1H) 8.2-8.6(m, 2H).                    38. The quaternised thiomethyl heterocycle salt was oxidised with MCPBA       in                                                                            CH.sub.2 Cl.sub.2 containing a catalytic amount of TFA at 0° C. to     room temperature for up                                                       to 4 hours, to give the corresponding sulphinyl compound, often also          containing sul-                                                               phone and sulphide, but not further purified.                             

EXAMPLE 107

An activated ester was prepared from(2-aminothiazol-4-yl)-(2-methoxyimino)acetic acid (1.1 eq.) by reactionwith hydroxybenzotriazole (1.1 eq.) and N,N'-dicyclohexylcarbodi-imide(1.1 eq.) in DMF, at room temperature for 2 hrs. To this ester was addeda solution of7-amino-3-[N-ethyl-N-(l-methyl-4-pyridinio)aminomethyl]ceph-3-em-4-carboxylate(1.0 eq.) in DMF and Et3N (2 eq.). The reaction mixture was stirred atroom temperature for 2 hrs. and filtered, and the solvents wereevaporated. The product,7-[2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-(N-ethyl)-[N-(1-methylpyridinio)]aminomethylceph-3-em-4-carboxylate,was purified by preparative HPLC eluting with MeOH/H₂ O/HOAc, 10:90:1.N.m.r. in solvent B: 1.0-1.3 (m, 3H), 3.0-3.8 (m, 4H), 3.9 (s, 3H), 3.95(s, 3H), 4.5-4.7 (m, 2H), 5.2 (d, 1H), 5.8 (d, 1H), 7.0 (s, 1H), 7.15(d, 2H), 8.2 (d, 2H).

The cephem starting material was obtained as follows:

3-Aminomethyl-7-(Boc-amino)ceph-3-em-4-carboxylic acid (1 eq.) wasdissolved in MEOH, with Et₃ N (1 eq.) and NaBH₃ CN (1 eq.) at roomtemperature. Acetaldehyde (1 eq.) was added over 15 minutes at roomtemperature, the solvent was evaporated, and the product,7-(Boc-amino)-3-ethylaminomethylceph-3-em-4-carboxylic acid, waspurified by preparative HPLC, eluting with MEOH/H₂ O/HOAC, 30:70:1.Yield 59%, contaminated with some disubstituted material.

The above product (1 eq.) was treated DMF/H₂ O (3:2) with4-chloro-1-methylpyridinium iodide (1 eq.) in presence of NAHCO₃ (3eq.). After 2 hrs. at room temperature, the solvents were evaporated andthe product was purified by preparative HPLC, eluting with MeOH/H₂O/HOAc, 30:70:1. Yield 20%. N.m.r. in d₆ -DMSO: 1.0-1.2 (m, 3H), 1.4 (s,9H), 2.8-3.8 (m, 4H), 3.9 (s, 3H), 4.2-4.8 (m, 2H), 4.9 (d, 1H), 5.2(dd, 1H), 7.7 (d, 2H), 8.2 (d, 2H).

The above product was deprotected by dissolving in TFA and leaving for1/2 hr. at room temperature. The TFA was evaporated, the residuetriturated with ether to give the required starting material. Yield 84%.N.m.r. in solvent B: 0.9-1.3 (m, 3H), 3.2-3.8 (m, 4H), 3.9 (s, 3H),4.5-4.8 (m, 2H), 5.2 (s, 2H), 7.15 (d, 2H), 8.25 (d, 2H).

EXAMPLES 108-115 Method A

The appropriate quaternised heterocyclic starting material (0.28mM)dissolved in a mixture of CH₃ CN/H₂ O (1:1; 2 ml) was added to a stirredsolution of3-ethylaminomethyl-7-[2-(2-aminothiazol-4-yl)-(Z)-2-(1-carboxycyclobut-1-yloxyimino)acetamido]ceph-3-em-4-carboxylicacid (0.28 mm) in CH₃ CN/H₂ O (1:1; 3 ml) at room temperature under anatmosphere of argon. Sodium bicarbonate (1.14 mM) was added to thereaction mixture which was stirred for 5 hr. and then poured into water(100 ml). The resulting solution was adjusted to pH 3.5 with acetic acidand then concentrated by rotary evaporation under vacuum at 20° C. Theresulting aqueous solution was filtered and then diluted with water (100ml) before loading on to an HP20SS column (20mm×350mm). The product waseluted from the resin by increasing amounts of CH₃ CN in H₂ O. Fractionscontaining the required product were combined and concentrated in vacuoand the aqueous residues freeze dried to give lyophilized solids.

Method B

The appropriate quaternised heterocyclic starting material (0.29 mM) indimethylformamide (2 ml) was added at room temperature to a stirredsolution of the N-ethylaminocephem-carboxylic acid of Method A (0.28 mM)in DMF (3 ml.). Triethylamine (0.56mm) was then added to the mixture andthe reaction was allowed to continue for 16 hr. The mixture was thenpoured into water (100 ml) and the pH adjusted to 3.5 with acetic acid.After filtering, the solution was applied to an HP20SS column (20 mm×350mm) and the product was eluted with increasing amounts of CH₃ CN in H₂O. The fractions containing the required product were pooled andconcentrated by rotary evaporation at 20° C. to give an aqueousconcentrate which was then freeze dried.

Using these general processes the following compounds were prepared:

    __________________________________________________________________________     ##STR135##                                                                   Example                                                                            R                     Yield %                                                                            Method                                                                             Footnotes                                __________________________________________________________________________    108                                                                                 ##STR136##           14   A    1, 2                                     109                                                                                 ##STR137##           31   A    3, 4                                     110                                                                                 ##STR138##           42   B    5, 6                                     111                                                                                 ##STR139##           44   B    7, 8                                     112                                                                                 ##STR140##           37   A    9, 10                                    113                                                                                 ##STR141##           16   B    11, 12                                   __________________________________________________________________________

The same general processes were also utilized with the correspondingaminomethyl intermediate to synthesize the following unalkylated3-aminomethyl derivatives:

    ______________________________________                                                                               Foot-                                  Example                                                                              R               Yield %  Method notes                                  ______________________________________                                        114                                                                                   ##STR142##     19       B      13. 14                                 115                                                                                   ##STR143##     25       A      15, 16                                 ______________________________________                                        Footnotes                                                                     1. The starting material was 6-chloro-1-methyl-1,2,4-                         triazolo[4,3-b]pyridazinium iodide.                                           2. n.m.r. in solvent A: 9.62(s, 1H); 8.48(d, 1H); 8.15(m, 1H); 6.73(s,        1H); 5.70(d, 1H); 5.03(d, 1H); 4.6(m, 2H); 4.14(s, 3H); 3.5-3.8(m,            2H); 3.15-3.5(ABq, 2H); 2.15-2.80(m, 6H); 1.05-1.25(m, 3H).                   3. The starting material was 3-chloro-1-methyl-pyridazinium                   iodide                                                                        4. n.m.r. in solvent A: 8.95(m, 1H); 8.05(m, 2H); 6.72(s, 1H);                5.75(d, 1H); 5.08(d, 1H); 4.45-4.80(ABq, 2H); 4.30(s, 1H); 3.56-              3.75(m, 2H); 3.20-3.55(ABq, 2H); 2.20-2.60(m, 6H); 1.05-1.30(m,               3H).                                                                          5. The starting material was 1-methyl-4-methylthiothieno[2,3-                 d]pyrimidine tetrafluoroborate.                                               6. n.m.r. in solvent A: 8.86(s, 1H); 7.93(d, 1H); 7.80(d, 1H); 6.74(s,        1H); 5.79(d, 1H); 5.11(d, 1H); 4.74-5.39(ABq, 2H); 4.02(m, 5H);               3.15-3.59(ABq, 2H); 2.20-2.48(m, 6H); 1.20-1.42(m, 3H).                       7. The starting material was 2,3-dihydro-7-methylthiothiazolo[2,3-            a]pyrimidinium tetrafluoroborate.                                             8. n.m.r. in solvent A: 8.3(m, 1H); 6.90-7.4(m, 1H); 6.74(s, 1H);             5.75(m, 1H); 5.05(m, 1H); 4.65-5.0(ABq, 2H); 4.50-4.65(m, 2H);                3.75-3.95(m, 2H); 3.55-3.75(t, 2H); 3.0-3.55(ABq, 2H), 2.20-                  2.5(m, 6H); 1.1(t, 3H).                                                       9. Prepared using 4-chloro-1-(trans-3-chloroalkyl)pyridinium                  tosylate as starting material (see Example 151, Footnote 38) and              method A, except that:                                                        DMF was used instead of CH.sub.3 CN and the reaction was worked               up by adjusting the pH to 7 with HOAc, concentrating to dryness               under vacuum at 20° and redissolving in water prior to HP20SS          chromatography.                                                               10. n.m.r. in solvent A: 8.22(d, 2H); 7.51(m, 1H); 7.10(m, 1H);               6.75(s, 1H); 6.73(d, 1H); 6.25(m, 1H); 5.73(d, 1H); 5.07(d, 1H);              4.81(d, 2H); 4.73, 4.49(ABq, 2H); 3.65(m, 2H); 3.45, 3.13(ABq,                2H); 2.36(m, 4H); 1.86(m, 2H)); 1.12(t, 3H).                                  11. The starting material was 1-(4-dimethylaminosulphonylbenzyl)-             4-methanesulphinyl pyridinium tetrafluoroborate, which was                    obtained as follows:                                                          4-Dimethylsulphamoylbenzyl bromide (0.005M) was mixed with                    4-methylthiopyridine (0.005M) and reacted exothermically, and                 was then left to stand overnight. The product was dissolved in                CH.sub.2 Cl.sub.2, and after standing for 3 hrs. was added dropwise to        rapidly stirred ether to precipitate 1-(4-dimethylsulphamoyl-                 benzyl)-4-methylthiopyridinium bromide, which was converted to                the corresponding tetrafluoroborate salt with silver tetra-                   fluoroborate.                                                                 The pyridinium tetrafluoroborate (1.34 mM) was dissolved in                   CH.sub.2 Cl.sub.2 (15 ml) and treated at 0° with sufficient TFA to     obtain                                                                        a solution, then MCPBA (1.34 mM) was added. The mixture was                   stirred at 0° for 15 minutes then at room temperature for 4 hrs.,      and the product was precipitated by the dropwise addition of ether            to give 1-(4-dimethylsulphamoyl)benzyl-4-methylsulphinyl-                     pyridinium tetrafluoroborate, the required starting material.                 12. n.m.r. in solvent A: 8.31(m, 2H); 7.3-7.90(m, 6H); 7.08(m,                1H); 6.73(s, 1H), 5.76(d, 1H); 5.48(s, 2H); 5.06(d, 1H); 4.35-                4.85(m, 2H), 3.40-3.80(m, 2H); 3.10-3.44(ABq, 2H); 2.56(s, 6H);               2.10-2.50(m, 6H); 1.0-1.25(m, 3H).                                            13. See Footnote 1.                                                           14. n.m.r. in solvent A: 9.65(s, 1H); 8.35(d, 1H); 7.51(d, 1H);               6.76(s, 1H); 5.80(d, 1H); 5.08(d, 1H); 4.05-4.50(ABq, 2H); 4.17(s,            3H); 3.36-3.76(ABq, 2H), 2.20-2.47(m, 6H)                                     15. See Footnote 5.                                                           16. n.m.r. in solvent A: 8.85(s, 1H); 7.90(m, 1H); 6.75(s, 1H);               5.81(d, 1H); 5.08(d, 1H); 4.46-4.95(ABq, 2H); 4.04(s, 3H);                    3.30-3.70(ABq, 2H), 2.17-2.46(m, 6H).                                     

The3-ethylaminomethyl-7-[2-(2-aminothiazol-4-yl)-(Z)-2-(1-carboxycyclobut-1-yloxyimino)acetamido]ceph-3-em-4-carboxylicacid used as starting material was prepared as follows:

3-Aminomethyl-7-[2-(2-aminothiazol-4-yl)-(Z)-2-(1-carboxycyclobut-1-yloxyimino)acetamido]ceph-3-em-4-carboxylicacid (10 g; 2.016×10⁻² mole) was stirred in MeOH (1.0 l.) and to thismixture was added triethylamine (2.8 ml; 2.016×10⁻² mole) dropwise,which resulted in a clear solution. Sodium cyanoborohydride (1.266 g;2.016×10⁻² mole) was added in one portion to the above solution followedby 8g of activated molecular sieves (4A). A solution of acetaldehyde(1.125 ml in 75 ml methanol) was added to the reaction mixture, under anargon atmosphere, over a period of 40 minutes using an infusion pump andthe status of the ensuing reaction was monitored by HPLC (Spherisorb5ODS, 4 mm×30 cm; MeOH/H₂ O/TFA (40:60:0.2 by volume), 2 ml/min flowrate and monitoring by u.v. at 270 nm). Reaction was continued for 1hr., the mixture was then filtered, and the filtrate was concentrated todryness on a rotary evaporator under high vacuum. The residue wasdissolved in water (100 ml) and loaded onto an HP20 macroreticular resin(3 l.) previously equilibrated with 0.2% TFA in water. The column waswashed with 0.2% TFA in water (2 l.) and then water (5 l.) followed byincreasing amounts of CH₃ CN in water. Fractions (2 l.) were collectedand the desired product eluted with 15% CH₃ CN/H₂ O. Fractions (21-23)containing the required product were pooled, and concentrated on arotary evaporator under high vacuum to give a clear solution (100 ml)which was freeze dried to yield 3 g lyophilised solid. Further fractionscontaining less pure amounts of the required product were also combinedand concentrated to give a crude sample (2 g) of the N-ethyl derivative.This crude sample was purified by medium pressure chromatography onHP20SS resin (350 mm×50 mm; flow rate 49 ml/min, 250 ml fractions) togive an additional pure sample (1 g) of the required intermediate.

n.m.r. in solvent A: 6.75 (s, 1H); 5.75 (d, 1H); 5.05 (d, 1H), 3.25-3.85(m, 4H=two AB quartets); 2.95 (q, 2H), 2.30-2.50 (m, 6H), 1.15 (t, 3H).

EXAMPLES 116-151

To a solution of3-aminomethyl-7-C2-(2-aminothiazol-4-yl)-2-C(Z)-1-carboxy-1-methylethoxyamino)acetamido]ceph-3-em-4-carboxylicacid (0.4 mmole) in DMF (11 ml) and water (3 ml) at 0° was added sodiumbicarbonate (4.8 mmole) dissolved in the minimum volume of waterfollowed by the appropriate 4-chloropyridinium toluene-p-sulphonate salt(0.4 mmole). After 1 hour the mixture was treated with HOAC (4.8 mmole)and evaporated to dryness under reduced pressure. The residue wasdissolved in water and purified by one of the following methods:

(a) HPLD on an octadecylsilane column using MeOH/water/HOAc 40:60:1 byvolume as eluant.

(b) Medium pressure liquid chromatography on a column of Diaion HP20SSresin (supplied commercially by Mitsubishi Chemical Industries Ltd.)using increasing concentrations of acetonitrile (from 0% to 30% v/v) inwater as eluant.

In each case the eluant containing the required product was evaporatedon a Buchi Rotavapor to remove the organic solvent and the resultingaqueous soution was dried by lyophilisation. Using this general methodthe following compounds were obtained:

    ______________________________________                                         ##STR144##                                                                   Ex-                                                                           am-                          Yield   Foot-                                    ple  R                       %       notes                                    ______________________________________                                        116                                                                                 ##STR145##             70       1                                       117                                                                                 ##STR146##             37       2                                       118                                                                                 ##STR147##             36       3                                       119                                                                                 ##STR148##             18       4                                       120                                                                                 ##STR149##             36       5                                       121                                                                                 ##STR150##             43       6                                       122                                                                                 ##STR151##             62       7                                       123                                                                                 ##STR152##             52       8                                       124                                                                                 ##STR153##             25       9                                       125                                                                                 ##STR154##             17      10                                       126                                                                                 ##STR155##             20      11                                       127                                                                                 ##STR156##             32      12                                       128                                                                                 ##STR157##             19      13                                       129                                                                                 ##STR158##             13      14                                       130                                                                                 ##STR159##             30      15                                       131                                                                                 ##STR160##              6      16                                       132                                                                                 ##STR161##             35      17                                       133                                                                                 ##STR162##             44      18                                       134                                                                                 ##STR163##              6      19                                       135                                                                                 ##STR164##             22      20                                       136                                                                                 ##STR165##             11      21                                       137                                                                                 ##STR166##             22      22                                       138                                                                                 ##STR167##             47      23, 24                                   139                                                                                 ##STR168##             23      25, 26                                   140                                                                                 ##STR169##             30      27                                       141                                                                                 ##STR170##             25      28                                       142                                                                                 ##STR171##             15      29                                       143                                                                                 ##STR172##              9      30                                       144                                                                                 ##STR173##             27      31                                       145                                                                                 ##STR174##             14      32                                       146                                                                                 ##STR175##             17      33                                       147                                                                                 ##STR176##             20      34                                       148                                                                                 ##STR177##             37      35                                       149                                                                                 ##STR178##             18      36                                       150                                                                                 ##STR179##              5      37                                       151                                                                                 ##STR180##             20      38                                       ______________________________________                                        Footnotes                                                                     1. n.m.r. in solvent A: 1.40(s, 6H); 3.43(d, 2H); 3.64(d, 1H); 4.30(d,        1H); 4.48(d, 1H); 5.15(d, 1H); 5.84(d, 1H); 6.74(s, 1H); 7.06(dd,             1H); 7.26(dd, 1H); 7.53(d, 1H); 7.66(q, 1H); 7.89(m, 1H); 8.34(dd,            1H); 8.54(dd, 1H).                                                            2. n.m.r. in solvent A: 1.46(s, 6H); 3.45(d, 1H); 3.66(d, 1H); 4.35(d,        1H); 4.51(d, 1H); 5.17(d, 1H); 5.86(d, 1H); 6.74(s, 1H); 7.10(d, 1H);         7.28(d, 1H); 7.86(d, 2H); 8.12(d, 2H); 8.46(d, 1H); 8.64(d, 1H).              3. n.m.r. in solvent A: 1.44(s, 6H); 3.45(d, 1H); 3.65(d, 1H); 4.31(d,        1H); 4.52(d, 1H); 5.15(d, 1H); 5.85(d, 1H); 6.75(s, 1H); 7.13(dd,             1H); 7.31(dd, 1H); 7.68-7.84(m, 2H); 7.90(dd, 1H); 8.07(dd, 1H);              8.33(dd, 1H); 8.54(dd, 1H).                                                   4. n.m.r. in solvent A: 1.40(s, 6H); 3.34(d, 1H); 3.57(d, 1H); 4.31(d,        1H); 4.56(d, 1H); 5.05(d, 1H); 5.72(d, 1H); 6.75(s, 1H); 7.09(dd,             1H); 7.53(dd, 1H); 8.20(dd, 1H); 8.34(d, 1H); 8.42(dd, 1H); 8.52(d,           1H); 8.60(dd, 1H).                                                            5. n.m.r. in solvent A: 1.35(s, 6H); 3.30(d, 1H); 3.57(d, 1H); 4.24(d,        1H); 4.44(d, 1H); 5.05(d, 1H); 5.70(d, 1H); 6.65(s, 1H); 7.00(d, 1H);         7.15(d, 1H); 7.80(d, 2H); 8.30(d, 2H); 8.30(d, 1H); 8.48(d, 1H).              6. A solution of 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-               methylethoxyimino)acetamido]-3-[1-(4-nitrophenyl)-4-pyridinio-                aminomethyl]ceph-3-em-4-carboxylate (110 mg) in a mixture of                  water (12 ml) and DMF (6 ml) was stirred for 1 hr. with 10%                   palladium on carbon in an atmosphere of hydrogen. The solution                was filtered through delite, and the filtrate was evaporated to               dryness. The resulting solid was washed with a mixture of water               and methanol (3:1 v/v, 3 ml), collected by filtration and dried in            vacuo to yield 3-[1-(4-aminophenyl)-4-pyridinio]aminomethyl-7-                [2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)-               acetamido]ceph-3-em-4-carboxylate (45 mg) having n.m.r. in                    solvent A: 1.45(s, 6H); 3.35(d, 1H); 3.60(d, 1H); 4.20(d, 1H);                4.40(d, 1H); 5.10(d, 1H); 5.78(d, 1H); 6.70(s, 1H); 6.80-                     8.50(complex, 8H).                                                            7. n.m.r. in solvent A: 1.40(s, 6H); 3.35(d, 1H); 3.65(d, 1H);                4.27(d, 1H); 4.50(d, 1H); 5.10(d, 1H); 5.78(d, 1H); 6.70(s, 1H);              7.00-7.30(m, 2H); 7.70-8.10(m, 2H); 8.20-8.60(m, 4H).                         8. The method described in Footnote 6 was repeated using 7-(2-                (2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)-                  acetamido]-3-[1-(3-nitrophenyl)-4-pyridinio]aminomethylceph-                  3-em-4-carboxylate to yield 3-[1-(3-aminophenyl)-4-pyridinio]-                aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-                    methylethoxyiminoacetamido]ceph-3-em-4-carboxylate having                     n.m.r. in solvent A: 1.44(s, 6H); 3.45(d, 1H); 3.65(d, 1H); 4.34(d,           1H); 4.47(d, 1H); 5.15(d, 1H); 5.84(d, 1H); 6.75(s, 1H); 6.90-7.45(m,         6H); 8.35(d, 1H); 8.54(d, 1H).                                                9. The toluene-p-sulphonate salt of 7-[2-(2-aminothiazol-4-yl)-2-             ((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-[1-(4-tert-                   butoxycarbonylphenyl)-4-pyridinio]aminomethylceph-3-em-4-                     carboxylate (320 mg) was dissolved with stirring in TFA (4 ml).               After 15 minutes the solution was evaporated to dryness and the               residue was purified by HPLC to yield the toluene-p-sulphonate                salt of 7-[2-(2-aminothiazol-4-yl)-2-[(Z)-1-carboxy-1-methyl-                 ethoxyimino)acetamido]-3-[1-(4-carboxyphenyl-4-pyridinio]amino-               methylceph-3-em-4-carboxylate (73 mg) having n.m.r. in solvent                A: 1.43(s, 6H); 2.27(s, 3H); 3.43(d, 1H); 3.64(d, 1H); 4.34(d, 1H);           4.53(d, 1H); 5.15(d, 1H); 5.82(d, 1H); 6.75(s, 1H); 7.12(d, 3H);              7.35(d, 1H); 7.50(d, 2H); 7.77(d, 2H); 8.16(d, 2H); 8.47(d, 1H);              8.65(d, 1H).                                                                  The tert-butyl ester used as starting material in the                         above process was obtained by the general method using 1-(4-tert-             butoxycarbonylphenyl)-4-chloropyridinium toluene-p-sulphonate                 as starting material.                                                         10. Ice cold TFA (5 ml) was added to a stirred mixture of anisole             (1 ml) and 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methyl-              ethoxyimino)acetamido]-3-[1-(4-tert-butoxyphenyl)-4-pyridinio]-               aminomethylceph-3-em-4-carboxylate (200 mg). The reaction                     mixture was allowed to warm to 10° C. and after 90 mins was            evaporated to dryness. Purification of the residue by HPLC                    yielded 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methyl-                 ethoxyimino)acetamido]-3-[1-(4-hydroxyphenyl)-4-pyridinio]-                   aminomethylceph-3-em-4-carboxylate having n.m.r. in solvent A:                1.50(s, 6H); 3.28(d, 1H); 3.60(d, 1H); 4.26(d, 1H); 4.60(d, 1H);              5.05(d, 1H); 5.74(d, 1H); 6.75(s, 1H); 6.93(d, 2H); 7.45(d, 2H);              6.9-7.5(m, 3H); 8.30(d, 1H); 8.45(d, 1H).                                     The tert-butyl ether used as starting material in the above process           was obtained by the general method using 1-(4-tert-butoxyphenyl)-             4-chloropyridinium toluene-p-sulphonate as starting material.                 11. n.m.r. in solvent A: 1.40(s, 6H); 3.45(d, 1H); 3.65(d, 1H);               4.35(d, 1H); 4.50(d, 1H); 5.15(d, 1H); 5.75(d, 1H); 6.75(s, 1H);              7.10(dd, 1H); 7.30(m, 1H); 7.90(d, 1H); 8.15(m, 1H); 8.60(d, 1H);             8.80(dd, 1H); 8.95(dd, 1H).                                                   12. n.m.r. in solvent A: 1.40(s, 6H); 3.35(d, 1H); 3.62(d, 1H);               4.25(d, 1H); 4.46(d, 1H); 5.05(d, 1H); 5.80(d, 1H); 6.75(s, 1H);              7.04(d, 1H); 7.10(d, 1H); 7.55(dd, 1H); 8.05(d, 1H); 8.35(d, 1H);             8.52(d, 1H); 8.65(d, 1H); 8.80(d, 1H).                                        13. n.m.r. in solvent A: 1.40(s, 6H); 3.34(d, 1H); 3.67(d, 1H),               4.36(d, 1H); 4.57(d, 1H); 5.07(d, 1H); 5.75(d, 1H); 6.74(s, 1H);              7.12(d, 1H); 7.55(d, 1H); 8.15(d, 1H); 8.60(dd, 1H); 8.82(d, 1H);             8.95(d, 1H); 9.05(d, 1H).                                                     14. n.m.r. in solvent A: 1.42(s, 6H); 3.34(d, 1H); 3.56(d, 1H);               4.37(d, 1H); 4.56(d, 1H); 5.07(d, 1H); 5.74(d, 1H); 6.74(s, 1H);              7.12(dd, 1H); 7.50(dd, 1H); 7.60(t, 1H); 8.98(d, 2H); 9.14(dd, 1H);           9.24(dd, 1H).                                                                 15. n.m.r. in solvent A: 1.45(s, 6H); 3.35(d, 1H); 3.58(d, 1H);               4.35(d, 1H); 4.60(d, 1H); 5.07(d, 1H); 5.74(d, 1H); 6.74(s, 1H);              7.14(dd, 1H); 7.58(dd, 1H); 8.26(d, 1H); 8.38(d, 1H); 8.76(dd, 1H);           8.86(dd, 1H).                                                                 16. n.m.r. in solvent A: 1.44(s, 6H); 3.30(d, 1H); 3.56(d, 1H);               4.30(d, 1H); 4.60(d, 1H); 5.07(d, 1H); 5.72(d, 1H); 6.72(s, 1H);              7.19(dd, 1H); 7.60(dd, 1H); 7.9-8.6(m, 2H); 8.86(m, 2H);                      9.37(q, 1H).                                                                  17. n.m.r. in solvent A: 1.45(s, 6H); 3.29(d, 1H); 3.54(d, 1H);               4.28(d, 1H); 4.56(d, 1H); 5.05(d, 1H); 5.71(d, 1H); 6.70(dd, 1H);             6.75(s, 1H); 6.88(dd, 1H); 7.06(dd, 1H); 7.58(dd, 1H); 7.76(dd, 1H);          8.44(dd, 1H); 8.60(dd, 1H).                                                   18. n.m.r. in solvent A: 1.44(s, 6H); 3.44(d, 1H); 3.64(d, 1H);               4.32(d, 1H); 4.47(d, 1H); 5.16(d, 1H); 5.84(d, 1H); 6.74(s, 1H);              7.10(dd, 1H); 7.05(dd, 1H); 7.25(dd, 1H); 7.85(dd, 1H); 8.36(dd,              1H); 8.41(dd, 1H); 8.58(dd, 1H).                                              19. n.m.r. in solvent A: 1.43(s, 6H); 3.40(d, 1H); 3.60(d, 1H);               4.30(d, 1H); 4.58(d, 1H); 5.13(d, 1H); 5.81(d, 1H) (d, 1H); 6.74(s,           1H); 7.00-7.15(m, 2H); 7.20(dd, 1H); 7.46(dd, 1H); 7.54(dd, 1H);              8.32(dd, 1H); 8.50(dd, 1H).                                                   20. n.m.r. in solvent A: 1.45(s, 6H); 3.46(d, 1H); 3.67(d, 1H);               4.34(d, 1H); 4.52(d, 1H); 5.17(d, 1H); 5.85(d, 1H); 6.75(s, 1H);              7.08(dd, 1H); 7.24(dd, 1H); 7.50(dd, 1H); 7.80(dd, 1H); 7.98(dd,              1H); 8.46(dd, 1H); 8.64(dd, 1H).                                              21. n.m.r. in solvent A: 1.45(s, 6H); 2.10(s, 3H); 3.30(d, 1H);               3.55(d, 1H); 4.35(d, 1H); 4.55(d, 1H); 5.05(d, 1H), 5.70(d, 1H);              6.75(s, 1H); 7.05(d, 2H); 7.15(d, 2H); 7.95(s, 1H); 8.60(dd, 2H);             8.70(dd, 2H).                                                                 22. n.m.r. in solvent A: 1.43(s, 6H); 3.33(d, 1H); 3.56(d, 1H),               4.35(d, 1H); 4.56(d, 1H); 5.06(d, 1H); 5.72(d, 1H), 6.75(s, 1H);              7.08(dd, 1H); 7.51(dd, 1H); 7.74(s, 2H); 8.66(dd, 1H); 8.75(dd, 1H).          23. Prepared by the general method using 1-(2-benzoxazolyl)-4-                methylsulphinylpyridinium chloride in place of the 4-chloropy-                ridinium toluene-p-sulphonate.                                                The pyridinium salt was prepared as follows.                                  A solution of 2-chlorobenzoxazole (1.38 g) and 4-methylthio-                  pyridine (1.13 g) in anhydrous methylene chloride was kept in the             dark overnight. The resulting crystalline precipitate of 1-(2-                benzoxazolyl)-4-methylthiopyridinium chloride (1.86 g) was                    collected by filtration, washed with anhydrous methylene chloride             and dried in vacuo.                                                           A solution of 3-chloroperbenzoic acid (127 mg, 85% pure) in                   methylene chloride (3 ml) was added dropwise to a stirred ice                 cold solution of 1-(2-benzoxazolyl)-4-methylthiopyridinium                    chloride (139 mg) in methylene chloride (3 ml) and TFA (0.10                  ml). The solution was allowed to warm to 20° C. After 40               minutes, toluene (2 ml) was added and the mixture was                         evaporated to dryness to yield a mixture of 1-(2-benzoxazolyl)-               4-methylsulphinylpyridinium chloride and 3-chlorobenzoic acid                 which was used directly in the general method.                                24. n.m.r. in solvent A: 1.45(s, 6H); 3.30(d, 1H); 3.65(d, 1H);               4.35(d, 1H); 4.62(d, 1H); 5.05(d, 1H); 5.70(d, 1H); 6.74(s, 1H);              7.00-7.90(m, 6H); 8.75(dd, 1H); 8.85(dd, 1H).                                 25. Prepared by the process described in Footnote 23, using                   2-chlorobenzothiazole as starting material in place of 2-chloro-              benzoxazole.                                                                  26. n.m.r. in solvent A: 1.40(s, 6H); 3.33(d, 1H); 3.56(d, 1H);               4.37(d, 1H); 4.64(d, 1H); 5.06(d, 1H); 5.72(d, 1H); 6.74(s, 1H);              7.15(d, 1H); 7.45-7.70(m, 3H); 8.00(d, 1H); 8.18(d, 1H); 8.80(d,              1H); 8.86(d, 1H).                                                             27. n.m.r. in solvent A: 1.45(s, 6H); 3.30(d, 1H); 3.55(d, 1H);               4.20(d, 1H); 4.45(d, 1H); 5.05(d, 1H); 5.15(d, 1H); 5.25(d, 1H);              5.70(d, 1H); 6.75(s, 1H); 6.80-7.20(m, 3H); 8.15(d, 1H); 8.30(d, 1H).         28. n.m.r. in solvent A: 1.45(s. 6H), 3.40(d, 1H); 3.52(d, 1H);               3.82(s, 3H); 4.28(d, 1H); 4.44(d, 1H); 5.04(d, 1H); 5.75(d, 1H);              6.75(s, 1H); 7.00-7.22(m, 3H); 7.35-7.62(m, 3H); 8.30(d, 1H);                 8.45(d, 1H).                                                                  29. n.m.r. in solvent A: 1.45(s, 6H); 2.10(s, 3H); 3.30(d, 1H);               3.65(d, 1H); 4.29(d, 1H); 4.59(d, 1H); 5.07(d, 1H); 5.71(d, 1H);              6.75(s, 1H); 7.07(d, 1H); 7.57(d, 2H); 7.57(d, 1H); 7.80(d, 2H);              8.35(d, 1H); 8.50(d, 1H).                                                     30. n.m.r. in solvent A: 1.35(s, 6H); 1.45(t, 3H); 3.48(d, 1H);               3.66(d, 1H); 4.30(m, 3H); 4.50(d, 1H); 5.17(d, 1H); 5.85(d, 1H);              6.75(s, 1H); 7.11(d, 1H); 7.36(d, 1H); 7.82(d, 2H); 9,15(d, 2H);              9.50(d, 1H); 9.70(d, 1H).                                                     31. n.m.r. in solvent A: 1.40(s, 6H); 2.80(s, 6H); 3.30(d, 1H);               3.58(d, 1H); 4.25(d, 1H); 4.50(d, 1H); 5.05(d, 1H); 5.70(d, 1H);              6.72(s, 1H); 7.00(d, 1H); 7.30(d, 1H); 7.60(m, 4H); 8.30(d, 1H);              8.45(d, 1H).                                                                  32. n.m.r. in solvent A: 1.45(s, 6H); 3.30(s, 3H); 3.45(d, 1H);               3.65(d, 1H); 4.35(d, 1H); 4.50(d, 1H); 5.15(d, 1H); 5.85(d, 1H);              6.75(s, 1H); 7.14(d, 1H); 7.33(d, 1H); 7.94(d, 2H); 8.16(d, 2H);              8.46(d, 1H); 8.66(d, 1H).                                                     33. n.m.r. spectrum in solvent A: 1.45(s, 6H), 3.35(d, 1H); 3.60(d,           1H); 4.35(d, 1H); 4.55(d, 1H); 5.05(d, 1H); 5.70(d, 1H), 6.70(s, 1H);         7.10(dd, 1H); 7.46(dd, 1H); 8.12(d, 1H); 8.50(d, 1H); 8.80(d, 1H);            8.94(d, 1H); 8.97(broad, 1H).                                                 34. n.m.r. spectrum in solvent A: 1.45(s, 6H); 2.70(s, 3H); 3.30(d,           1H); 3.55(d, 1H); 4.30(d, 1H); 4.60(d, 1H); 5.05(d, 1H); 5.70(d, 1H);         6.75(s, 1H); 7.10(d, 1H); 7.60(d, 1H); 7.80(d, 2H); 8.15(d, 2H);              8.35(d, 1H), 8.55(d, 1H).                                                     35. n.m.r. in solvent A: 1.40(s, 6H); 2.08(m, 2H); 2.50(t, 2H);               3.26(d, 1H); 3.50(d, 1H); 4.15(t, 2H); 4.20(d, 1H); 4.42(d, 1H);              5.02(d, 1H); 5.69(d, 1H); 6.73(d, 1H); 6.94(d, 1H); 7.35(d, 1H);              9.10(d, 1H); 8.25(d, 1H).                                                     36. n.m.r. in solvent A: 1.46(s, 6H); 3.26(d, 1H); 3.50(d, 1H);               4.20(d, 1H); 4.44(d, 1H); 4.80(d, 2H); 5.05(d, 1H); 5.20(d, 1H);              5.32(d, 1H); 5.72(d, 1H); 5.90(d t, 1H); 6.3-6.6(m, 2H); 6.74(s,              1H); 6.94(d, 1H); 7.38(d, 1H); 8.16(d, 1H); 8.25(d, 1H).                      37. n.m.r. in solvent A: 1.40(s, 6H); 3.40(d, 1H); 3.60(d, 1H);               4.25(d, 1H); 4.40(d, 1H); 4.90(d, 2H); 5.15(d, 1H); 5.80(d, 1H);              6.20(m, 1H); 6.65(d, 1H); 6.75(d, 1H); 6.90(d, 1H); 7.10(d, 1H);              8.05(d, 1H); 8.20(d, 1H).                                                     38. n.m.r. in solvent A: 1.40(s, 6H); 3.40(d, 1H); 3.60(d, 1H);               4.25(d, 1H); 4.35(d, 1H); 4.80(d, 2H); 5.15(d, 1H); 5.85(d, 1H);              6.20(m, 1H); 6.20(m, 1H); 6.70(d, 1H); 6.75(s, 1H); 6.90(d, 1H);              7.10(d, 1H); 8.10(d, 1H); 8.25(d, 1H).                                    

The 1-substituted-4-chloropyridinium toluene-p-sulphonate salts used asstarting materials in the above processes may be prepared as follows:

A solution of the appropriate 1-substituted-4-pyridone (2.5 mmole) andtoluene-p-sulphonyl chloride (3.8 mmole) in DMF (10 ml) was stirred at100° C. for 10 mins. The reaction mixture was cooled and evaporated todryness. Trituration of the residue with ether yielded the required4-chloropyridinium toluene-p-sulphonate salt as a solid which was usedwithout further purification in the preparation of the final product.Using the general process the following compounds were prepared:

    ______________________________________                                         ##STR181##                                                                                             Starting Material                                   R               Footnotes for Example Number                                  ______________________________________                                        3,4-difluorophenyl                                                                             1        116                                                 4-cyanophenyl    2        117                                                 2-cyanophenyl    3        118                                                 3,4-dicyanophenyl                                                                              3        119                                                 4-nitrophenyl    3        120, 121                                            3-nitrophenyl    4        122, 123                                            4-tert-butoxycarbonylphenyl                                                                    5        124                                                 4-tert-butoxyphenyl                                                                            6        125                                                 2-pyridyl        7        126                                                 3-pyridyl        4        127                                                 5-cyano-2-pyridyl                                                                              7        128                                                 2-pyrimidinyl    7        129                                                 6-chloro-3-pyridazinyl                                                                         7        130                                                 3-pyridazinyl    8        131                                                 2-furyl          9        132                                                 3-furyl         10        133                                                 2-thienyl       11        134                                                 3-thienyl       11        135                                                 4-methyl-2-oxazolyl                                                                           12        136                                                 2-thiazolyl     13        137                                                 vinyl                     140                                                 4-methoxyphenyl  4        141                                                 4-acetamidophenyl                                                                             14        142                                                 4-ethoxycarbonylphenyl                                                                         5        143                                                 4-dimethylaminocarboxy-                                                                       15        144                                                 phenyl                                                                        4-methylsulphonylphenyl                                                                       16        145                                                 5-trifluoromethyl-2-pyridyl                                                                    7        146                                                 4-acetoxyphenyl  5        147                                                 3-cyanopropyl   17        148                                                 penta-2,4-dienyl                                                                              18        149                                                 cis-3-chlorallyl                                                                              19        150                                                 trans-3-chloroallyl                                                                           19        151                                                 ______________________________________                                        Footnotes                                                                     1. The starting material was prepared as follows:                             A mixture of alpha-pyrone (880 mg.), 3,4-difluoroaniline                      (1.54 g.) and concentrated hydrochloric acid (0.8 ml.)                        in water (10 ml.) was stirred under reflux for 2 hours.                       The reaction mixture was cooled and basified with                             aqueous ammonia solution. The precipitated product was                        filtered off, washed with cold ethyl acetate (10 ml.)                         and dried in vacuo to yield 1-(3,4-difluorophenyl)-4-                         pyridone (1.10 g.) as a buff solid.                                           2. The starting material was prepared as follows:                             Sodium hydride (410 mg. of a 1% dispersion in mineral                         oil) was placed in an argon atmosphere, washed free of                        oil with  -n-pentane and suspended in DMF (10 ml.). Solid                     4-hydroxypyridine (1.00 g.) was added in small portions                       to the suspension. Stirring was continued for 15                              minutes after the evolution hydrogen gas had ceased and                       then a solution of 4-fluorobenzonitrile (1.27 g.) in DMF                      (3 ml.) was added. The resulting mixture was stirred at                       110° C. for 30 minutes and then poured whilst still hot                into cold water (60 ml.). After cooling for 30 minutes                        in ice the crystalline precipitate of 1-(4-cyanophenyl)-                      4-pyridone (1.45 g.) was collected by filtration, washed                      with water, dried in vacuo and recrystallised from                            EtOAc.                                                                        3. The pyridone starting material was prepared by                             the method described in Footnote 2, using the                                 appropriate substituted chlorobenzene in place of                             4-fluorobenzonitrile.                                                         4. The starting material was prepared by the                                  method described in Example 2 using the appropriate                           aniline in place of 4-fluoroaniline.                                          5. The pyridone starting material was prepared by                             the method described in Footnote 2, using the                                 appropriate substituted fluorobenzene in place of                             4-fluorobenzonitrile.                                                         6. The pyridone starting material was prepared as                             follows:                                                                      A mixture of alpha-pyridone (440 mg.), 4-tert-butoxy-                         aniline (755 mg.) and HOAc (0.262 ml.) was stirred at                         100° C. for 10 minutes in an argon atmosphere. The                     cooled reaction mixture was evaporated to dryness, using                      the azeotropic evaporation of added toluene to remove                         the last traces of HOAc. The residue was purified by                          chromatography on a column of Kieselgel 60, eluting with                      methylene chloride, then 95:5 v/v methylene chloride;                         methanol, to give 1-(4-tert-butoxyphenyl)-4-pyridone                          (340 mg.) having n.m.r. in CDC1.sub.3 :                                       1.40(s, 9H), 6.50(d, 2H), 7.0-7.3(m, 4H), 7.60                                (d, 2H).                                                                      7. The pyridone starting material was prepared                                by the method described in Footnote 2, using the                              appropriate 2-chloroheterocycle in place of 4-fluoro-                         benzonitrile.                                                                 8. The pyridone starting material was prepared as                             follows:                                                                      A solution of 1-(6-chloro-3-pyridazinyl)-4-pyridone                           (1.00 g.) and sodium acetate (0.50 g.) in EtOH (50 ml.)                       and water (3 ml.) containing 10% palladium on carbon                          (200 mg.) was stirred for 75 minutes in an atmosphere                         of hydrogen.                                                                  The mixture was filtered through kieselguhr                                   and the filtrate was evaporated to dryness.                                   Recrystallisation of the residue from EtOAc yielded                           1-(3-pyridazinyl)-4-pyridone, (350 mg.) having n.m.r. in                      solvent A:                                                                    6.35(d, 2H), 7.95(q, 1H), 8.20(q, 1H), 8.50(d, 2H),                           9.30(q, 1H).                                                                  9. The pyridone starting material was prepared as                             follows:                                                                      Sodium hydride (1.69 g. of a 1% dispersion in mineral                         oil) was placed in an argon atmosphere, washed free of                        oil with  -n-pentane and suspended in DMSO (27 ml.).                          Solid 4-hydroxypyridine (4.12 g.) was added in small                          portions to the stirred suspension. Stirring was                              continued for 15 minutes after the evolution of hydrogen                      gas had ceased. Powdered methyl 5-nitro-2-furoate                             (6.18 g.) was then added and stirring was continued for                       48 hours. The reaction mixture was evaporated to                              dryness and the dark brown residue was extracted with                         95:5 v/v methylene chloride/MeOH (3 × 100 ml.). The                     extracts were passed through a column of Kieselgel 60                         (50 mg.) and the eluent was evaporated to dryness. The                        residue was dissolved in methylene chloride (100 ml.)                         and the solution was filtered. Evaporation of the                             filtrate to a volume of ca 20 ml. deposited pale brown                        crystals of the methyl ester, 1-(5-methoxycarbonyl-                           2-furyl)-4-pyridone (3.07 g.), having m.p. 194 - 6° C.                 Chromatography of the mother liquor on Kieselgel 60                           afforded a further crop (863 mg.) of the same product.                        The methyl ester (3.95 g.) was stirred in                                     methanol (78 ml.) in an argon atmosphere, while a                             solution of potassium hydroxide (4.87 g.) in water                            (39 ml.) was added. The methyl ester rapidly dissolved.                       Stirring was continued overnight and the reaction                             mixture was evaporated to dryness. The residue was                            dissolved in the minimum volume of water and acidified                        with N-hydrochloric acid to pH. 1. The resulting                              precipitate was isolated by centrifugation, washed with                       water then acetone, and dried in vacuo to yield the                           acid, 1-(5-carboxy-2-furyl)-4-pyridone (3.74 g.)                              A mixture of the acid (3.74 g.), copper bronze                                (1.64 g.) and quinoline (8 ml.) was stirred at 210° C. in              an argon atmosphere until the evolution of carbon                             dioxide ceased (ca. 30 minutes). The cooled reaction                          mixture was dissolved in EtOAc and filtered through                           kieselguhr. The filtrate was evaporated to dryness and                        the residue was purified by chromatography on Kieselgel                       60 (30 g.) eluting initially with methylene chloride to                       remove quinoline then with 95:5 v/v methylene                                 chloride/MeOH to afford 1-(2-furyl)-4-pyridone (2.20 g.).                     10. The pyridone starting material was prepared as                            follows:                                                                      A mixture of 3-bromofuran (2.50 g.), freshly sublimed                         4-hydroxypyridine (1.61 g.), copper powder (2.20 g.) and                      powdered anhydrous potassium carbonate (4.80 g.) in DMF                       (25 ml.) was stirred at 150° C. for 2 hours in an argon                atmosphere. The cooled reaction mixture was filtered                          through kieselguhr and the filtrate was evaporated to                         dryness. The residue was extracted with warm 95:5 v/v                         chloroform/MeOH (100 ml.). The resulting solution was                         applied to a column of Kieselgel 60 (30 g.). Elution                          with the same solvent gave 1-(3-furyl)-4-pyridone                             (1.17 g.).                                                                    11. The pyridone starting material was prepared by                            the method described in footnote 10, using the                                appropriate bromothiophene in place of 3-bromofuran.                          12. The pyridone starting material was prepared by                            the method described in footnote 2, using 4-methyl-2-                         methylsulphinyloxazole in place of 4-fluorobenzo-                             nitrile.                                                                      13. The pyridone starting material was prepared by                            the method described in footnote 2, using 2-bromo-                            thiazole in place of 4-fluorobenzonitrile.                                    14. The starting material was prepared as follows:                            A solution of 1-(4-nitrophenyl)-4-pyridone (500 mg) in                        EtOH (5 ml) and DMF (5 ml) was stirred at 80° C. for 30                minutes with 10% palladium on carbon (150 mg) in an                           atmosphere of hydrogen. The reaction mixture was                              cooled and filtered through kieselguhr. The filtrate was                      evaporated to dryness and the solid residue was stirred                       overnight with a mixture of acetic anhydride (1 ml),                          pyridine (3 ml) and DMF (3 ml). The reaction mixture was                      evaporated to dryness to yield 1-(4-acetamidophenyl)-4-                       pyridone (420 mg.) as a white solid.                                          15. The pyridone starting material was prepared as                            follows:                                                                      A mixture of 1-(4-ethoxycarbonylphenyl)-4-pyridone                            (1.0 g) and 33% w/v dimethylamine in ethanol was stirred                      during the dropwise addition of a solution of sodium                          ethoxide [prepared by the addition of sodium metal                            (50 mg) to ethanol (2.5 ml)]. Stirring was continued                          overnight, then the reaction mixture was evaporated to                        dryness to yield 1-(4-dimethylcarbamoylphenyl)-4-                             pyridone which was used without purification.                                 16. The pyridone starting material was prepared as                            follows:                                                                      Using the method described in Example 2,4-methyl-                             thioaniline was converted into 1-(4-methylthiophenyl)-4-                      pyridone. A mixture of the pyridone (1.80 mg), HOAc                           (14 ml) and 100 volumes aqueous hydrogen peroxide (4.5 ml)                    were stirred at 70° C. for 2 hours. The cooled reaction                mixture was diluted with water and extracted with ethyl                       acetate. The ethyl acetate solution was washed with                           aqueous sodium metabisulphite, dried with sodium                              sulphate, and evaporated to yield 1-(4-methylsulphonyl-                       phenyl)-4-pyridone (1.15 g) which was used without                            further purification.                                                         17. The pyridone starting material was prepared by                            the method described in footnote 2, using 4-bromobutyro-                      nitrile in place of 4-fluorobenzonitrile.                                     18. The pyridone starting material was prepared as                            follows:                                                                      A mixture of 2-chloropenta-2,4-diene (1.49 g), 4-hydroxy-                     pyridine (1.39 g), powdered anhydrous potassium carbonate                     (4.14 g) and DMF (10 ml) was stirred for 90 minutes at                        80° C. in an argon atmosphere. The reaction mixture was                cooled and the DMF was evaporated. The residue was                            extracted with 9:1 v.v methylene chloride/methanol                            (200 ml). The extacts were filtered through a pad of                          Kieselgel 60 (30 g) and the filtrates were evaporated to                      dryness to give a brown oil. Chromatography of this                           oil on Kieselgel 60, eluting initially with methylene                         chloride, then 19:1 v/v methylene chloride/methanol,                          afforded 1-(penta-2,4-dienyl)-4-pyridone (1.36 g) as a                        pale orange oil.                                                              19. The pyridone starting materials were prepared                             as follows:                                                                   A solution of 1,3-dichloropropene (cis/trans mixture,                         1.97 ml) and 4-hydroxypyridine (2.00 g) in acetone (25 ml)                    was stirred with powdered anhydrous potassium carbonate                       (2.90 g) for 1 hour under reflux. Further portions of                         1,3-dichloropropene (1.97 ml) and potassium carbonate                         (2.90 g) were added and the reaction mixture was stirred                      for a further hour under reflux. The cooled reaction                          mixture was filtered and the solid residue was washed                         well with acetone. The combined acetone filtrates were                        evaporated to dryness. The oily residue was                                   chromatographed on a column of Kieselgel 60 (100 g)                           eluting with methylene chloride, then 19:1 v/v methylene                      chloride/methanol, to separate the cis and trans isomers                      of the product, 2-(3-chlorallyl)-4-pyridone.                              

EXAMPLES 152-158

To a solution of3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-[(Z)-1-carboxy-1-methylethoxyamino)acetamido]ceph-3-em-4-carboxylicacid (0.4 mmole) in DMF (11 ml.) and water (3 ml) at 0° was added sodiumbicarbonate (4.8 mmole) dissolved in the minimum volume of water,followed by a solution of the appropriate pyridinium salt (0.5 mmole) inDMF (5 ml). After 1 hour the mixture was treated with HOAc (4.8 mmole)and evaporated to dryness under reduced pressure. The residue wasdissolved in water and purified by chromatography on Diaion HP20SSresin.

Using this general process the following compounds were prepared

    __________________________________________________________________________     ##STR182##                                                                   Example                                                                            R                       Yield %                                                                            Footnotes                                   __________________________________________________________________________    152                                                                                 ##STR183##             10   1                                           153                                                                                 ##STR184##             16   2                                           154                                                                                 ##STR185##             30   3                                           155                                                                                 ##STR186##             24   4                                           156                                                                                 ##STR187##             44   5                                           157                                                                                 ##STR188##             15   6                                           158                                                                                 ##STR189##              8   7                                           __________________________________________________________________________    1. n.m.r. in solvent A: 1.40(s, 6H); 3.30(d, 1H); 3.50(d, 1H); 4.20(d,        1H); 4.40(d, 1H);                                                             4.95(d, 2H); 5.05(d, 1H); 5.70(d, 1H); 6.70(s, 1H); 6.95(d, 1H); 7.25(d,      1H); 7.65(d,                                                                  2H); 8.10(d, 1H); 8.15(d, 2H); 8.30(d, 1H).                                   2. n.m.r. in solvent A: 1.45(s, 6H); 3.27(d 1H); 3.50(d, 1H); 4.21(d,         1H); 4.43(d, 1H);                                                             4.95(d, 2H); 5.04(d, 1H); 5.68(d, 1H); 6.28(m, 1H); 6.74(s, 1H);              6.90-7.45(m, 3H);                                                             8.02(d, 1H); 8.20(d, 1H).                                                     3. n.m.r. in solvent A: 1.40(m, 12H); 3.24(d, 1H); 3.45(m, 5H); 4.20(d,       1H); 4.48(d,                                                                  1H); 4.90 (broad, 2H); 5.05(d, 1H); 5.70(d, 1H); 6.70(s, 1H); 6.80(m,         1H); 6.95(m,                                                                  2H); 7.50(dd, 1H); 8.10(d, 1H); 8.28(d, 1H).                                  4. n.m.r. in solvent A: 1.44(s, 6H); 3.55(m 10H); 4.25(d, 1H); 4.40(d,        1H); 4.90(d,                                                                  2H); 5.15(d, 1H); 5.83(d, 1H); 6.65(m, 2H); 6.75(s, 1H); 6.95(d, 1H);         7.07(d, 1H);                                                                  8.10(d, 1H); 8.27(d, 1H).                                                     5. n.m.r. in solvent A: 0.85(t, 3H), 1.35(m, 2H); 1.40(s, 6H); 3.05(m,        2H); 3.25(d,                                                                  1H); 3.50(d, 1H); 4.20(d, 1H); 4.45(d, 1H); 4.90(d, 1H); 5.05(d, 1H);         5.70(d, 1H);                                                                  5.85(d, 1H); 6.75(s, 1H); 6.80(m, 1H); 6.95(dd, 1H); 7.40(dd, 1H);            8.10(d, 1H); 8.20                                                             (d, 1H).                                                                      6. n.m.r. in solvent A: 1.40(s, 6H); 3.25(d, 1H); 3.50(d, 1H); 4.20(d,        1H); 4.50(d, 1H);                                                             4.95(d, 2H); 5.05,(d, 1H); 5.70(d, 1H); 5.80(d, 1H); 6.75(s, 1H); 6.80(m,     1H); 7.00                                                                     (dd, 1H); 7.45(dd, 1H); 8.10(d, 1H); 8.25(d, 1H).                             7. n.m.r. in solvent A: 1.45(s, 6H); 1.95(s, 3H); 3.40(d, 1H); 3.60(d,        1H); 4.25(d, 1H);                                                             4.40(d, 1H); 4.90(s, 2H); 5.15(d, 1H); 5.30(s, 1H); 5.85(d, 1H); 6.75(s,      1H); 6.95(d,                                                                  1H); 7.10(d, 1H); 8.00(d, 1H); 8.20(d, 1H).                               

The pyridinium salts used as starting materials in the above process maybe prepared as follows:

A solution of 3-chloroperbenzoic acid (1.05 mmole) in anhydrousmethylene chloride (2 ml) was added dropwise to a stirred solution atthe appropriate 1-substituted-4-methylthiopyridinium salt (0.5 mmole) inmethylene chloride (5 ml) and TFA (0.1 ml) at 0°. The reaction mixturewas allowed to warm to room temperature over 1 hour and was thenevaporated to dryness. The residue was washed with ether to remove3-chlorobenzoic acid and the insoluble residue, a mixture of theappropriate 4-methylsulphinyl- and 4-methylsulphonylpyridinium salts,was used directly in the above process.

Using this general procedure the following compounds were prepared:

    ______________________________________                                         ##STR190##                                                                                                   Starting Material                             R             X      Footnotes  for Example No.                               ______________________________________                                        4-nitrocinnamyl                                                                             Cl     1          152                                           trans-3-cyanoallyl                                                                          BF.sub.4                                                                             2          153                                           trans-3-(2-piperidino-                                                                      Br     3          154                                           carboxy)allyl                                                                 trans-3-(1-morpholino-                                                                      Br     4          155                                           carboxy)allyl                                                                 trans-3-(N-propyl-                                                                          Br     4          156                                           aminocarboxy)allyl                                                            trans-3-(amino-                                                                             Br     4          157                                           carboxy)allyl                                                                  .sub.-- E-3-cyano-2-methyl-                                                                Br     4          158                                           allyl                                                                         ______________________________________                                        Footnotes                                                                     1. The 1-(4-nitrocinnamyl)-4-methylthiopyridinium                             chloride starting material was prepared as follows. A                         solution of 4-nitrocinnamyl chloride (181 mg) and                             4-methylthiopyridine (125 mg) in acetonitrile (1 ml) was                      kept in the dark for 48 hours. The solvent was                                evaporated and the residue was triturated with ether to                       give the required starting material as an off-white                           solid (170 mg).                                                               2. The 1-(trans-3-cyanoallyl)-4-methylthio-                                   pyridinium tetrafluoroborate starting material was                            prepared as follows. A solution of 4-bromocrotono-                            nitrile (660 mg) and 4-methylthiopyridine (565 mg) in                         anhydrous methylene chloride (3 ml) was kept in the dark                      for 48 hours. The resulting black crystalline solid                           (888 mg) was filtered off and dried in vacuo. This                            solid was dissolved in a mixture of water (20 ml) and DMF                     (10 ml). To this stirred solution was added a solution of                     silver tetrafluoroborate (636 mg) in water (3 ml). After                      5 minutes the solution was filtered through celite and                        evaporated to dryness. The resulting gum was dissolved                        in water (20 ml), refiltered and freeze-dried to yield                        the starting material as a fluffy orange solid (810 mg).                      3. The 1-[trans-3(1-piperidinocarboxy)]allyl-4-                               methylthiopyridinium bromide starting material was                            prepared as follows. A solution of trans-3-(1-                                piperidinocarboxy)allyl bromide (440 mg) and 4-methyl-                        thiopyridine (240 mg) in acetonitrile (5 ml) was kept in                      the dark for 24 hours. The solvent was evaporated and                         the residue was washed with ether to afford the required                      starting material as a gum.                                                   4. The required starting material was prepared,                               using the procedure in Footnote 3, by reacting 4-methyl-                      thiopyridine with the appropriate substituted allyl                           bromide.                                                                  

EXAMPLES 159-160

Using the general processes described in Example 116, with theappropriate 3-aminomethylcephalosporin and pyridinium salt startingmaterials the following compounds were prepared.

    ______________________________________                                         ##STR191##                                                                                              Yield                                              Example                                                                              R                   %       Footnotes                                  ______________________________________                                        159                                                                                   ##STR192##         17      1                                          160                                                                                   ##STR193##         15      2                                          ______________________________________                                        Footnotes                                                                     1. n.m.r. in solvent A: 2.40(m, 6H); 3.40(d,                                  1H); 3.60(d, 1H); 4.25(d, 1H); 4.38(d, 1H); 4.80(d,                           1H); 5.15(d, 1H); 5.85(d, 1H); 6.20(m, 1H); 6.70(d,                           1H); 6.75(s, 1H); 6.90(d, 1H); 7.10(d, 1H); 8.05(d,                           1H); 8.25(d, 1H).                                                             2. n.m.r. in solvent A: 1.96(s, 3H); 2.40(m,                                  6H); 3.42(d, 1H); 3.65(d, 1H); 4.27(d, 1H); 4.40(d,                           1H); 4.95(s, 2H); 5.16(d, 1H); 5.32(s, 1H); 5.85(d,                           1H); 6.74(s, 1H); 6.97(d, 1H); 7.10(d, 1H); 8.04(d,                           1H); 8.25(d, 1H).                                                         

EXAMPLES 161-171

The general process described in Example 1 was repeated using theappropriate heterocyclic starting material. The reactions were carriedout in DMF/water mixtures in the presence of NaHCO₃ at the temperaturein the range ambient to 75° for 0.4-4 hours. The product was purified ona octadecylsilane column and the following compounds were thus prepared.

    __________________________________________________________________________     ##STR194##                                                                                           Yield                                                 Example R               %      Footnotes                                      __________________________________________________________________________    161     CH.sub.3        7      1, 2, 3                                        162     NHCH.sub.2 CHCH.sub.2                                                                         18     4, 5, 6                                        163     NHCH(CH.sub.3).sub.2                                                                          22     7, 8, 9                                        154     N(CH.sub.3).sub.2                                                                             25     10, 11, 12                                     165                                                                                    ##STR195##     14     13, 14, 15                                     166                                                                                    ##STR196##     4.5    16, 17, 18                                     167     NHCH.sub.2 CH.sub. 2 NH.sub.2                                                                 12     19, 20, 21, 22                                 168     NHCH.sub.2 CH.sub.2 OH                                                                        11     23, 24, 25                                     169     NHCH.sub.2 CH.sub.2 OCH.sub.3                                                                  6     26, 27, 28                                     170     SCH.sub.3       32     29, 30, 31                                     171     SCH.sub.2 CH.sub.2 NHCOCH.sub.3                                                               20     32, 33, 34                                     __________________________________________________________________________    Footnotes                                                                     1. The starting material was prepared by reaction of 3-chloro-6-methylpyri    dazine with trimethloxonium tetrafluoroborate in CH.sub.2 Cl.sub.2 15         hours at ambient                                                              temperature to give 3-chloro-1,6-dimethylpyridazinium tetrafluoroborate.      2. HPLC eluant MeOH/water/HOAc 15:84:1, v/v/v.                                3. n.m.r. in solvent B; 1.53(br.s, 6H); 2.62(s, 3H); 3.6(m, 2H); 4.14(s,      3H); 5.15(d,                                                                  1H); 4.85(d, 1H); 7.05(s, 1H); 7.55(d, 1H); 7.85(d, 1H).                      4. (a) The starting material was obtained as follows. Reaction of 3,6-        difluoropyridazine with trimethyloxonium tetrafluoroborate gave 3,6-          difluoro-1-methylpyridazinium tetrafluoroborate.                              (b) To this compound (1.5 mmole) in acetonitrile (5 ml) was added a           solution of allylamine (1.5 mmole) in acetonitrile (3 ml) and                 NaHCO.sub.3. After 2 hours at ambient temperature the mixture was             filtered, and the filtrate was evaporated to yield an oil, which              crystallised to give 3-fluoro-1-methyl-6-(allylamino)-pyridazinium            tetrafluoroborate.                                                            5. HPLC eluant MeOH/water/HOAc 25:74:1 v/v/v.                                 6. n.m.r. in solvent B: 1.56(br.s, 6H); 3.55(m, 2H); 3.78(s, 3H); 4.0(m,      2H); 3.95(d, 1H); 4.5(d, 1H); 5.15(m, 3H); 5.83(m, 2H); 7.06(s, 1H);          7.42(s, 2H).                                                                  7. The starting material was prepared by reaction of 3,6-difluoro-1-methyl    pyridazinium tetrafluoroborate (Footnote 4a) with 2 equivalents of            isopropylamine in acetonitrile at ambient temperature, to give 3-fluoro-      1-methyl-6-isopropylamino-pyridazinium tetrafluoroborate.                     8. HPLC eluant MeOH/water/HOAc 30:69:1 v/v/v.                                 9. n.m.r. in solvent B: 1.21(s, 3H); 1.28(s, 3H); 1.54(br.s, 6H); 3.5(m,      2H); 3.76(s,                                                                  3H); 3.85(d, 1H); 4.0(m, 1H); 4.45(d, 1H); 5.15(d, 1H); 5.83(d, 1H);          7.05(s,                                                                       1H); 7.4(d, 1H); 7.67(d, 1H).                                                 10. The starting material was prepared as follows. To a stirred solution      of                                                                            3,6-difluoro-1-methyl-pyridazinium tetrafluoroborate (2.00 mmoles,            Footnote                                                                      4a) in acetonitrile under argon at room temperature was added MgO (2.0        mmoles) followed by a solution of dimethylamine in toluene (4.0 mmoles).      After 2 hours, the mixture was filtered, and the filtrate was evaporated      to                                                                            an oil, which crystallised after trituration with ether, to give              3-fluoro-1-                                                                   methyl-6-(N,N-dimethylamino)pyridazinium tetrafluoroborate.                   11. HPLC eluant MeOH/water/HOAc 22.5:77.5:1 v/v/v                             12. n.m.r. in solvent B: 1.53(br.s, 6H); 3.06(s, 6H); 3.45(d, 1H); 3.7(d,     1H); 3.89                                                                     (s, 3H); 4.05(d, 1H); 4.5(d, 1H); 5.13(d, 1H); 5.80(d, 1H); 7.05(s, 1H);      7.32(d,                                                                       1H); 7.52(d, 1H).                                                             13. The starting material was prepared by the method described in             Footnote 7,                                                                   using p-nitrobenzyl-amine, to give 3-fluoro-1-methyl-6-(p-nitrobenzylamino    )-                                                                            pyridazinium tetrafluoroborate.                                               14. HPLC eluant MeOH/water/HOAc 35:64:1 v/v/v.                                15. n.m.r. in solvent B: 1.53(br.s, 6H); 3.5(m, 2H); 3.86(s, 3H); 3.95(d,     1H);                                                                          4.45(d, 1H); 5.14(d, 1H); 5.8(d, 1H); 7.05(s, 1H); 7.36(br.s, 2H);            7.62(d, 2H);                                                                  8.18(d, 2H).                                                                  16. The starting material was prepared by the method described in             Footnote 4 to                                                                 give 3-fluoro-1-methyl-6-(2-thenylamino)pyridazinium tetrafluoroborate.       17. HPLC eluant MeOH/aqueous ammonium carbonate (2 g/l) 30:70 v/v.            18. n.m.r. in solvent B: 1.53(s, 6H); 3.55(m, 2H); 3.93(s, 3H); 3.95(d,       1H); 4.45(d,                                                                  1H); 4.95(s, 2H); 5.15(d, 1H); 5.8(d, 1H); 7.05(s, 1H); 6.97-7.7(m, 5H).      19. The starting material was prepared by the method described in             Footnote 4                                                                    using N-Boc ethylene diamine.                                                 20. HPLC eluant MeOH/aqueous ammonium carbonate (2 g/l), 30:70 v/v.           21. Cleavage of the Boc protecting group was achieved after the HPLC by       treatment with TFA for 5 minutes.                                             22. n.m.r. in solvent B: 1.56(s, 6H); 3.1(m, 2H); 3.85(m, 4H); 3.94(s,        3H); 4.64(m,                                                                  2H); 5.27(d, 1H); 5.98(d, 1H); 7.06(s, 1H); 8.05(d, 1H); 8.85(d, 1H).         23. The starting material was prepared by a slow addition of a solution       of                                                                            ethanolamine in acetontrile under argon, followed by NaHCO.sub.3. After       1 hour at ambient temperature the mixture was filtered, and the filtrate      was                                                                           evaporated to an oil, which crystallised to give 3-fluoro-6-(2-hydroxyethy    l-                                                                            amino)-1-methyl pyridazinium tetrafluoroborate.                               24. HPLC eluant MeOH/water/HOAc 20:79:1 v/v/v.                                25. n.m.r. in solvent B: 1.53(s, 6H); 3.54(m, 6H); 3.73(s, 3H); 3.95(d,       1H); 4.4(d,                                                                   1H); 5.1(d, 1H); 5.8(d, 1H); 7.06(s, 1H); 7.35(d, 1H); 7.55(d, 1H).           26. The starting material, 3-fluoro-6-(2-methoxy-ethylamino)-1-methyl-pyri    dazinium tetrafluorobate was prepared by the method described in Foot-        note 7 using 2-methoxyethylamine.                                             27. HPLC eluant MeOH/water/HOAc 25:74:1 v/v/v.                                28. n.m.r. in solvent B: 1.53(s, 6H); 3.23(s, 3H); 3.5(m, 6H); 3.73(s,        3H); 3.95(d,                                                                  1H); 4.5(d, 1H); 5.15(d, 1H); 3.85(d, 1H); 7.07(s, 1H); 7.4(d, 1H);           7.7(d, 1H).                                                                   29. The starting material was obtained by reaction of 3,6-difluoro-1-methy    lpyri-                                                                        dazinium tetrafluoroborate (Footnote 4a) with sodium thiomethylate in         acetonitrile for 1 hour at ambient temperature to give 3-fluoro-1-methyl-6    methylthiopyridazinium tetrafluoroborate.                                     30. The crude condensation product was purified by chromatography on          Diaion                                                                        HP20 resin, eluting with increasing proportions of MeOH in water.             31. n.m.r. in solvent B: 1.54(br.s, 6H); 2.76(s, 3H); 3.56(m, 2H);            4.07(s, 3H);                                                                  4.02(d, 1H); 4.55(d, 1H); 5.15(d, 1H); 5.85(d, 1H); 7.06(s, 1H); 7.6(d,       1H); 7.95(d, 1H).                                                             32. The starting material was prepared by the method described in             Footnote 7,                                                                   using 2-acetamido-1-mercaptoethane to give 3-fluoro-1-methyl-6-(2-acetamid    o-                                                                            ethylthio)pyridazinium tetrafluoroborate as a paste.                          33. HPLC eluant MeOH/water/HOAc 25:74:1 v/v/v.                                34. n.m.r. in solvent B: 1.54(s, 6H); 1.83(s, 3H); 3.2-3.8(m, 6H); 4.0(s,     3H);                                                                          4.6(m, 2H); 5.19(d, 1H); 5.85(d, 1H); 7.0(s, 1H); 7.93(s, 2H).            

EXAMPLES 172-178

The general process described in Example 1 was repeated using theappropriate 3-aminomethylcephalosporin derivative and the appropriateheterocycle. The following compounds were obtained:

    __________________________________________________________________________     ##STR197##                                                                   Example                                                                       No.  R.sup.1  R.sup.2                                                                            R.sup.3      Yield                                                                             Footnote                                  __________________________________________________________________________    172  CH.sub.3 H    CH.sub.3     30  1, 2, 3                                   173  CH.sub.2 CH.sub.2 Cl                                                                   H    CH.sub.3     24  1, 4, 5                                   174  C(CH.sub.3).sub.2 CO.sub.2 H                                                           H                                                                                   ##STR198##  14  6, 7, 8                                   175  "        H    CH.sub.2 CHCH.sub.2                                                                        18  9, 10, 11                                 176  "        H                                                                                   ##STR199##  23  12, 13, 14                                177                                                                                 ##STR200##                                                                            C.sub.2 H.sub.5                                                                    CH.sub.3     12  1, 15, 16                                 178                                                                                 ##STR201##                                                                            H    CH.sub.3     32  1, 17, 18                                 __________________________________________________________________________    Footnotes                                                                     1. The starting material was 6-amino-3-fluoro-1-methylpyridazinium            tetrafluoroborate                                                             see Example 13, Footnote 16.                                                  2. HPLC eluant MeOH/water/HOAc, 15:84:1 v/v/v.                                3. n.m.r. in solvent B: 3.25-3.8(m, 2H); 3.7(s, 3H); 4.0(s, 3H); 3.8(d,       1H); 4.5(d, 1H);                                                              5.12(d, 1H); 5.76(d, 1H); 7.05(s, 1H); 7.25(s, 2H).                           4. HPLC eluant MeOH/water/HOAc, 20:79:1, v/v/v.                               5. n.m.r. in solvent B: 3.55(m, 2H); 3.7(s, 3H); 3.9-4.4(m, 6H); 5.15(d,      1H); 5.76(d, 1H);                                                             7.05(s, 1H); 7.3(s, 2H).                                                      6. The starting material may be prepared as follows: 3,6-difluoropyridazin    e was mixed                                                                   with a solution of ammonia (10 equivalents) in ethanol, and heated in a       sealed tube                                                                   for 3 hours at 80-85° C. The solvent was evaporated and                6-amino-3-fluoropyri-                                                         dazine was extracted from the residue with EtOAc in a Soxhlet apparatus       for 3.5 hours.                                                                This compound in EtOH was further treated with p-nitrobenzyl bromide for      2.5 hours                                                                     at 40° C. The solvent was evaporated and the residue was washed        twice with anhydrous                                                          ether, to give 6-amino-3-fluoro-1-(4-nitrobenzyl)pyridazinium bromide.        7. HPLC eluant MeOH/water/HOAc, 35:64:1, v/v/v.                               8. n.m.r. in solvent B: 1.57(br.s., 6H); 3.5(m, 2H); 4.0(d, 1H); 4.45(d,      1H); 5.15(d, 1H);                                                             5.45(br.s, 2H); 5.87(d, 1H); 7.1(s, 1H); 7.47(s, 2H); 7.65(d, 2H);            8.35(d, 2H).                                                                  9. The starting material may be prepared as follows: 6-amino-3-fluoropyrid    azine (2.5                                                                    mmoles; Footnote 6), and 2 ml of allyl bromide in the minimum of              nitromethane were                                                             heated to 60° C. for 3 hours. Evaporation of the solvent, washing      of the residue                                                                with ether and drying under vacuum over P.sub.2 O.sub.5  gave                 1-allyl-6-amino-3-                                                            fluoropyridazinium bromide.                                                   10. HPLC eluant MeOH/water/HOAc, 30:69:1, v/v/v.                              11. n.m.r. in solvent B: 1.6(br.s, 6H); 3.57(m, 2H); 3.8-4.9(m, 4H);          5.1-5.45(m, 3H);                                                              5.85(m, 2H); 7.17(s, 2H); 7.4(s, 2H).                                         12. The starting material was prepared as follows: 6-amino-3-fluoropyridaz    ine (1.15                                                                     mmoles; Footnote 6) and alpha'-chloro-alpha,alpha,alpha-trifluoro-m-xylene     in the                                                                       minimum of DMF were heated to 60° C. for 4 hours. Evaporation of       the solvent                                                                   and trituration of the residue with anhydrous either gave                     6-amino-3-fluoro-1-(3-                                                        trifluoromethylbenzyl)-pyridazinium chloride.                                 13. HPLC eluant MeOH/water/HOAC, 45:54:1, v/v/v.                              14. n.m.r. in solvent B: 1.54(s, 6H); 3.5(m, 2H); 4.03(d, 1H); 4.45(d,        1H); 5.11(d, 1H);                                                             5.43(d, 1H); 5.9(d, 1H); 7.1(s, 1H); 7.45(s, 2H); 7.62-7.95(m, 4H).           15. HPLC eluant MeOH/water/HOAc, 25-30:74-69:1 v/v/v.                         16. n.m.r. in solvent B: 1.07(t, 3H); 1.9-3.0(m, 6H); 3.46(m, 4H);            4.25(d, 1H); 4.6(d,                                                           1H); 5.2(d, 1H); 5.86(d, 1H); 6.98(s, 1H); 7.4(d, 1H); 7.76(d, 2H).           17. HPLC eluant MeOH/water/HOAc, 25-30:74-69:1 v/v/v.                         18. n.m.r. in solvent B: 1.72(m, 4H); 2.15(m, 4H); 3.55(m, 2H); 3.7(s,        3H); 4.05(d, 1H);                                                             4.55(d, 1H); 5.15(d, 1H); 5.83(d, 1H); 7.06(s, 1H); 7.3(s, 2H).           

EXAMPLES 179-180

The process described in Example 1 was repeated, using the appropriateheterocycle as starting material, to give the following compounds:

    ______________________________________                                         ##STR202##                                                                   Example                                                                       No.     R                 Yield %  Footnotes                                  ______________________________________                                        179                                                                                    ##STR203##       15       1, 2, 3, 4                                 180                                                                                    ##STR204##        9       5, 6, 7, 8                                 ______________________________________                                        1. The starting material was obtained by reaction of                          3-chloro-5,6,7,8-tetrahydrocinnoline (see Journal of Org.                     Chemistry 1955, Vol. 20, p.707) with trimethyloxonium tetra-                  fluoroborate in CH.sub.2 Cl.sub.2 overnight.                                  2. The condensation was performed in water at pH 7.6                          (ambient temperature) with NaHCO.sub.3 as base.                               3. HPLC eluant, MeOH/water/HOAc, 30-40:69-59:1, v/v/v.                        4. n.m.r. in solvent B: 1.54(s, 6H); 1.86(m, 4H); 2.81(m, 4H);                3.60(br.s, 2H); 3.96(s, 3H); 4.55(br.s, 2H); 5.16(d, 1H);                     5.88(d, 1H); 7.04(s, 1H); 7.73(s, 1H).                                        5. The starting heterocycle may be prepared as follows: To a                  stirred solution of 7.7-dichlorobicyclo-[3,2,0]heptan-6-one                   (see Tetrahedron, 1971, Vol. 27, p.615)(52.7 mmoles) in                       MeOH(25 ml) at 0° C. was added dropwise hydrazine hydrate              (3.3 ml.). Stirring was continued at 0° C. for 0.75 hours,             the solvent was evaporated, the residue was taken up in water                 and extracted with CH.sub.2 Cl.sub.2, and the organic phases                  were combined, washed with water and dried (MgSO.sub.4).                      Evaporation of the solvent gave cis-1,1-dichloromethylcyclo-                  pentane carbohydrazide (yield 54%) having the following                       n.m.r. in CDCl.sub.3 : 2.0(m, 6H); 2.8(m, 2H); 3.92(br.s,                     2H); 5.96(d, 1H); 7.0(br.s, 1H). The above hydrazide                          (28.7 mmoles) was dissolved in aqueous EtOH (40 ml.; 3:1 v/v)                 and heated at reflux for 1.75 hours. The reaction mixture                     was diluted with water and extracted with                                     CH.sub.2 Cl.sub.2. The combined CH.sub.2 Cl.sub.2 extracts                    were washed with water and dried (MgSO.sub. 4), the solvent was               evaporated to a small volume and ether was added to give                      4,5-dihydro-4,5-trimethylenepyridazin-3(2H)-one (yield 87%).                  N.m.r. in CDCl.sub.3 : 1.5-2.4(m, 6H); 2.6-3.0(m, 2H);                        6.95(d, 1H); 7.7(br.s, 1H). This dihydropyridazinone derivative               (17.7 mmoles) was dissolved in HOAc (15 ml.) and bromine                      (17.6 mmoles) was added slowly with stirring. The reaction                    mixture was then heated 0.4 hours at 100° C., cooled and               the HOAc evaporated. The residue was taken up in water and                    the pH adjusted to 10 with 12N NaOH. After stirring for 3                     hours at room temperature, the reaction mixture was extracted                 with CH.sub.2 Cl.sub.2, the combined CH.sub.2 Cl.sub.2                        extracts were washed with water, dried (MgSO.sub.4), and                      the solvent was evaporated. The crude product was applied to                  a column of Kieselgel 60 (120 g). Elution with ether-MeOH,                    5-7:95-93 v/v, gave 4,5-trimethylenepyridazin-                                3(2H)-one in 24% yield. N.m.r. in CDCl.sub.3 : 2.13(q, 2H);                   2.91(t, 4H); 7.78(s, 1H). The above pyridazinone derivative                   (13.5 mmoles) was treated with 15 ml. of phosphorous oxychloride              at 80° C. for 2 hours. After evaporation to dryness, the               residue was taken up in water, neutralised with NaHCO.sub.3                   and extracted with CH.sub.2 Cl.sub.2. The CH.sub.2 Cl.sub.2                   was evaporated and the residue was applied to a column of                     Kieselgel 60 (50 g). Elution with ether/MeOH, 95:5 v/v, gave                  3-chloro-4,5-trimethylenepyridazine (yield 42%). N.m.r. in                    CDCl.sub.3 : 2,2(q, 2H); 3.06(t, 2H); 3.08(t, 2H);                            9.02(s, 1H). This compound was then treated with                              trimethyloxonium tetrafluoroborate in CH.sub.2 Cl.sub.2                       at ambient temperature for 0.5 hour to give a 9:1 mixture                     of 1-methyl and 2-methyl-4,5-trimethylenepyridazinium                         tetrafluoroborate in 90% yield. N.m.r. in CDCl.sub.3 of                       the 1-methyl derivative is: 2.39(q, 2H); 3.26(t, 2H);                         3.43(t, 2H); 4.59(s, 3H); 9.51(s, 2H).                                        6. The condensation was performed in DMF/water at                             60° C. for 6 hours in the presence of NaHCO.sub.3.                     7. HPLC eluant: MeOH/water/HOAc, 25:74:1, v/v/v.                              8. n.m.r. in solvent B: 1.51(s, 3H); 1.54(s, 3H); 2.17(m, 2H);                2.9(m, 4H); 3.52(m, 2H); 4.21(s, 3H); 4.67(m, 1H); 4.84(m, 1H);               5.1(d, 1H); 5.82(d, 1H); 7.05(s, 1H); 8.95(s, 1H).                        

EXAMPLES 181-191

The general process described in Example 1 was repeated using theappropriate 3-aminomethyl-cephalosporin derivative and the appropriateheterocycle. The following compounds were obtained:

    __________________________________________________________________________     ##STR205##                                                                   Example No.                                                                          R.sup.1  R.sup.2                                                                         R.sup.3          Yield %                                                                            Footnote                              __________________________________________________________________________    181    C(CH.sub.3).sub.2 CO.sub.2 H                                                           H                                                                                ##STR206##      13   1, 2, 3                               182    C(CH.sub.3).sub.2 CO.sub.2 H                                                           H                                                                                ##STR207##      20   4, 5, 6                               183    "        Et                                                                               ##STR208##      24   4, 7, 8                               184                                                                                   ##STR209##                                                                            Et                                                                               ##STR210##      31   4, 9, 10                              185                                                                                   ##STR211##                                                                            H                                                                                ##STR212##      60   4, 11, 12                             186    C(CH.sub.3).sub.2 CO.sub.2 H                                                           H                                                                                ##STR213##      27   13, 14, 15                            187    "        Et                                                                               ##STR214##      36   13, 16, 17                            188                                                                                   ##STR215##                                                                            H                                                                                ##STR216##      54   13, 18, 19                            189    C(CH.sub.3).sub.2 CO.sub.2 H                                                           H                                                                                ##STR217##      35   20, 21, 22                            190                                                                                   ##STR218##                                                                            H                                                                                ##STR219##           23, 24, 25                            191    "        H                                                                                ##STR220##           26, 27, 28                            __________________________________________________________________________    1. 6-Fluoro-2,3-dihydro-1H-imidazo(1,2,3)-pyridazinium bromide was            prepared according to the                                                     procedure described in Croat. Chem. Acta 41, 135 (1969) using                 3,6-difluoropyridazine as starting                                            material. The hydrobromide salt in MeOH was further treated with              diazomethane to liberate the                                                  free base, 6-fluoro-2,3-dihydroimidazo(1,2-b)pyridazine. Upon evaporation     of the MeOH, the                                                              compound was dissolved in CH.sub.2 Cl.sub.2 /nitromethane (5:3 v/v) and       trimethyloxonium                                                              tetrafluoroborate was added to the reaction mixture. After 4 hours at         ambient temperature,                                                          the mixture was filtered, and the filtrate was evaporated to give             6-fluoro-2,3-dihydro-1-                                                       methylimidazo(1,2-b)pyridazinium tetrafluoroborate.                           2. HPLC eluant, MeOH/water/HOAc, 25:74:1 v/v/v.                               3. n.m.r. in solvent B: 1.54(s, 6H); 2.99(s, 3H); 3.2-4.6(m, 8H); 5.13(d,     1H); 5.82(d, 1H);                                                             7.05(s, 1H); 7.4(d, 1H); 7.5(d, 1H).                                          4. The starting material was 6-chloro-thiazolo-[3,2-b]pyridazinium            perchlorate,                                                                  (see J. Org Chem 34, 996, (1969).                                             5. HPLC eluant, MeOH/water HOAc, 20:79:1, v/v/v.                              6. n.m.r. in solvent B: 1.55(s, 6H); 3.3(d, 1H); 3.55(d, 1H); 3.95(d,         1H); 4.4(d, 1H);                                                              5.15(d, 1H); 5.55(d, 1H); 7.45(d, 1H); 8.47-8.6(m, 3H).                       7. The product was purified by chromatography on Diaion HP20 resin,           eluting with increasing                                                       proportions of CH.sub.3 CN in water.                                          8. n.m.r. in solvent B: 1.16(br t, 3H); 1.51(s, 6H); 3.5(m, 2H); 3.6(m,       2H); 4.45(d, 1H);                                                             3.65(d, 1H); 5.18(d, 1H); 5.85(d, 1H); 7.0(s, 1H); 7.9(d, 1H); 8.54(d,        1H); 8.66(d, 1H);                                                             8.7(d, 1H).                                                                   9. HPLC eluant, MeOH/water/HOAc, 20-30:79-69:1 v/v/v.                         10. n.m.r. in solvent B: 1.15(br t, 3H); 1.91-2.4(m, 6H); 3.6(m, 4H);         4.5(d, 1H);                                                                   4.8(d, 1H); 5.17(d, 1H); 5.85(d, 1H); 6.98(s, 1H); 7.85(d, 1H); 8.65(d,       1H); 8.5(d, 1H);                                                              8.6(d, 1H).                                                                   11. HPLC eluant, MeOH/water/HOAc, 30:69:1, v/v/v.                             12. n.m.r. in solvent B: 1.7(m, 4H); 2.1(m, 4H); 3.5(d, 1H); 3.7(d, 1H);      4.1(d, 1H); 4.6(d, 1H);                                                       5.14(d, 1H); 5.84(d, 1H); 7.04(s, 1H); 7.45(d, 1H); 8.6(d, 1H); 8.47(d,       1H); 8.52(d, 1H).                                                             13. The starting material was 6-chloro-3-methylthiozolo[3,2-b]pyridazinium     perchlorate                                                                  (see J. Org. Chem. 34, 996(1964)).                                            14. HPLC eluant, MeOH/water/HOAc, 25:74:1, v/v/v.                             15. n.m.r. in solvent B: 1.52(s, 3H); 1.54(s, 3H); 3.55(m, 2H); 4.1(d,        1H); 4.65(d, 1H);                                                             5,15(d, 1H); 5.85(d, 1H); 7.0(s, 1H); 7.47(d, 1H)); 8.62(d, 1H); 8.23(s,      1H).                                                                          16. HPLC eluant, MeOH/water/HOAc, 30:69:1, v/v/v.                             17. n.m.r. in solvent B: 1.15(br.t, 3H); 1.5(br.s, 6H); 2.51(s, 3H);          3.4(q, 2H); 3.65(m, 2H);                                                      4.5(d, 1H); 4.8(d, 1H); 5.17(d, 1H); 5.87(d, 1H); 7.0(s, 1H); 7.87(d,         1H); 8.64(d, 1H); 8.2(s, 1H).                                                 18. HPLC eluant MeOH/water/HOAc, 30:69:1, v/v/v.                              19. n.m.r. in solvent B: 1.7(m, 4H); 2.1(m, 4H); 2.52(s, 3H); 3.56(d,         1H); 3.6(d, 1H); 4.3(d, 1H);                                                  4.6(d, 1H); 5.15(d, 1H); 5.86(d, 1H); 7.04(s, 1H); 7.47(d, 1H); 8.61(d,       1H); 8.61(d, 1H); 8.22(s, 1H).                                                20. The starting material was prepared by treating 6-fluoroimidazo(1,2-b)p    yridazine, (obtained by                                                       a process described in Tetrahedron, 23, 387 (1967), with trimethyloxonium     tetrafluoroborate in                                                          CH.sub.2 Cl.sub.2 at ambient temperature for 5 hours. The precipitate was     filtered, to give                                                             6-fluoro-1-methylimidazo(1,2-b)pyridazinium tetrafluoroborate.                21. HPLC eluant, MeOH/water/HOAc, 20:79:1, v/v/v.                             22. n.m.r. in solvent B: 1.56(br.s, 6H); 3.61(m, 2H); 3.98(s, 3H); 4.1(d,     1H); 4.6(d, 1H); 5.15(d, 1H);                                                 5.83(d, 1H); 7.02(s, 1H); 7.31(d, 1H); 8.04(d, 1H); 8.09(d, 1H); 8.21(d,      1H).                                                                          23. For starting material see Example 229, Footnote 2.                        24. HPLC eluant was MeOH/water/HOAc, 25:74:1, v/v/v.                          25. n.m.r. in solvent B: 1.7(m, 4H); 2.14(m, 4H); 3.48(d, 1H); 3.7(d,         1H); 4.15(s, 3H); 4.14(d, 1H);                                                4.45(d, 1H); 5.14(d, 1H); 5.85(d, 1H); 7.05(s, 1H); 7.52(d, 1H); 8.35(d,      1H); 9.47(s, 1H).                                                             26. For starting material, see Example 222, Footnote 5.                       27. HPLC eluant was MeOH/water/HOAc, 30:69:1, v/v/v.                          28. n.m.r. in solvent B: 1.7(m, 4H); 2.15(m, 4H); 2.44(d, 1H); 2.65(d,        1H); 4.05(s, 3H); 4.55(d, 1H);                                                4.95(d, 1H); 5.15(d, 1H); 5.82(d, 1H); 7.05(s, 1H); 7.92(s, 2H); 8.9(s,       1H).                                                                      

EXAMPLE 192 ##STR221##

The starting material was 3-fluoro-6-methoxy-1-methyl-pyridaziniumtetrafluoroborate, which was obtained by treatment of6-fluoro-2-methylpyridazin-3-one with trimethyloxonium tetrafluoroboratein CH₂ CL₂ at ambient temperature.

The condensation reaction was carried out in DMF/water in the presenceof NaHCO₃ at ambient temperature for 0.5 hours. Yield 12%.

HPLC eluant, MeOH/water/HOAc, 25:74:1, v/v/v.

n.m.r. in solvent B: 1.54 (s, 6H); 3.6 (br.s, 2H); 3.93 (s, 3H); 3.45(d, 1H); 3.85 (d, 1H), 5.16 (d, 1H); 5.88 (d, 1H); 7.04 (s, 1H);7.98-8.17 (m, 2H).

EXAMPLE 193 ##STR222##

This compound was obtained as follows: To 5-amino-3-chloropyridazine(see Yakugaku Zasshi 82, 857-60, (1962); Chem. Abstracts 59, 1631j) innitromethane was added trimethyloxonium tetrafluoroborate. After 3 hoursat ambient temperature the solvent was evaporated, and the ether wasadded to give a mixture of 5-amino-3-chloro-1-methylpyridazinium and5-amino-3-chloro-2-methylpyridazinium tetrafluoroborates, which wereused without further separation. The standard procedure was used for thecondensation, which was carried out in a DMF/water mixture in thepresence of NaHCO₃ at 70° C. for 1.25 hours. The final compound wasworked up by HPLC using MeOH/water/HOAc, 22.5:76.5:1 v/v/v, as eluant.Yield 25%. n.m.r. of the single isomer product in solvent B: 1.53 (br.s,6H); 3.59 (m, 2H); 3.83 (s, 3H); 4.56 (m, 2H); 5.15 (d, 1H); 5.9 (d,1H); 6.23 (d, 1H); 7.0 (s, 1H); 7.92 (d, 1H).

EXAMPLES 194-195

The general process described in Example 1 was repeated, using theappropriate 3-aminomethylcephalosporin derivative and the appropriateheterocycle, to give the following compounds:

    ______________________________________                                         ##STR223##                                                                   Example No.                                                                             R              Yield %   Footnotes                                  ______________________________________                                        194                                                                                      ##STR224##    37        1, 2, 3                                    195                                                                                      ##STR225##    23        4, 5, 6                                    ______________________________________                                        Footnotes:                                                                    1. For the quaternary heterocyclic starting material, see Example             182, Footnote 4.                                                              2. HPLC eluant, MeOH/water/HOAc, 20-25:79-74:1, v/v/v.                        3. n.m.r. in solvent B: 1.48(s, 6H); 3.45(d, 1H); 3.71(d, 1H);                4.11(d, 1H); 4.57(d, 1H); 5.12(d, 1H); 5.84(d, 1H); 7.46(d, 1H);              8.47(d, 1H); 8.57(d, 2H).                                                     4. For the quarternary heterocyclic starting material, see Example            13, Footnote 6.                                                               5. HPLC eluant, MeOH/water/HOAc, 20:79:1, v/v/v.                              6. n.m.r. in solvent B: 1.47(s, 6H); 3.5(m, 2H); 3.6(s, 3H);                  3.91(d, 1H); 4.42(d, 1H); 5.09(d, 1H); 5.83(d, 1H); 7.26(s, 2H).              7. The 3-aminomethyl cephalosporin starting material was obtained             by adding the corresponding known 3-azidomethyl cephalosporin                 derivative to 90% v/v aqueous TFA and stirring for 3 hours at                 ambient temperature. After cooling at 0°, Raney nickel                 (wet 2.0 g) was added and the mixture was stirred for 0.5 hours at            0° and 1 hour at ambient temperature. The mixture was filtered,        the filtrate evaporated and the crude product purified by                     chromatography on a Diaion HP 20 column, eluting with                         increasing proportions of acetonitrile in water. Appropriate                  fractions were combined, evaporated to a small volume and                     freez-dried to give the required compound (0.81 g; yield 43%)                 having the following n.m.r. in solvent B: 1.49(s, 6H);                        3.5-4.0(m, 4H); 5.18(d, 1H); 5.9(d, 1H).                                  

EXAMPLES 196-218

The general procedure described in Examples 1-4 was used, except thatthe reaction was carried out at ambient temperature for 5 hours beforequenching with HOAc. The appropriate 3-aminomethylcephalosporin wasused, the reaction was worked up by chromatography on Diaion CHP20Presin to purify. The following compounds were made:

    __________________________________________________________________________     ##STR226##                                                                   Example No.                                                                          R.sup.1   R.sup.2          Yield %                                                                            Footnotes                              __________________________________________________________________________    196    CH.sub.2 CO.sub.2 H                                                                      ##STR227##      46   1, 2                                   197    CH.sub.2 CO.sub.2 H                                                                      ##STR228##      40   3, 4                                   198                                                                                   ##STR229##                                                                              ##STR230##      34   1, 5, 6                                199                                                                                   ##STR231##                                                                              ##STR232##      40   1, 6, 7                                200                                                                                   ##STR233##                                                                              ##STR234##      28   3, 6, 8                                201                                                                                   ##STR235##                                                                              ##STR236##      22   3, 6, 9                                202                                                                                   ##STR237##                                                                              ##STR238##      29   3, 10                                  203                                                                                   ##STR239##                                                                              ##STR240##      20   11, 12                                 204    CH.sub.2 CONHCH.sub.3                                                                    ##STR241##      67   1, 13, 14                              205    CH.sub.2 CON(CH.sub.3).sub.2                                                             ##STR242##      64   1, 15, 16                              206    CH.sub.2 CONHCH.sub.2 CF.sub.3                                                           ##STR243##      57   1, 17, 18                              207                                                                                   ##STR244##                                                                              ##STR245##      69   1, 19, 20                              208    C.sub.2 H.sub.5                                                                          ##STR246##      18   11, 21                                 209                                                                                   ##STR247##                                                                              ##STR248##      60   1, 22, 23                              210                                                                                   ##STR249##                                                                              ##STR250##      46   1, 23, 24                              211                                                                                   ##STR251##                                                                              ##STR252##      33   3, 25                                  212                                                                                   ##STR253##                                                                              ##STR254##      69   26, 27                                 213                                                                                   ##STR255##                                                                              ##STR256##      57   28, 29                                 214                                                                                   ##STR257##                                                                              ##STR258##      56   30, 31                                 215                                                                                   ##STR259##                                                                              ##STR260##      53   30, 32                                 216                                                                                   ##STR261##                                                                              ##STR262##      61   30, 33                                 217                                                                                   ##STR263##                                                                              ##STR264##      42   34, 35                                 218                                                                                   ##STR265##                                                                              ##STR266##      52   1, 36                                  __________________________________________________________________________    Footnotes                                                                     1. Starting material was 3-chloro-1-methylpyridazinium iodide.                2. n.m.r. in solvent A: 3.36(d, 1H); 3.59(d, 1H); 4.08(d, 1H); 4.24(s,        3H); 4.48(d, 1H); 4.53(s, 2H);                                                5.03(d, 1H); 5.71(d, 1H); 6.8(s, 1H); 7.6(m, 1H); 7.88(m, 1H); 8.88(m,        1H).                                                                          3. Starting material was 7-methylthiothiazolo-[3,2-a]pyrimidinium             tetrafluoroborate.                                                            4. n.m.r. in solvent A: 3.35(d, 1H); 3.6(d, 1H); 4.25(d, 1H); 4.51(s,         2H); 4.64(d, 1H); 5.03(d, 1H);                                                5.73(d, 1H); 6.81(s, 1H); 7.04(d, 1H); 7.65(d, 1H); 8.08(d, 1H); 8.79(d,      1H).                                                                          5. n.m.r. in solvent A: 1.4(d, 3H); 3.39(d, 1H); 3.61(d, 1H); 4.08(d,         1H); 4.23(s, 3H); 4.53(d, 1H);                                                4.6(q, 1H); 5.06(d, 1H); 5.8(d, 1H); 6.81(s, 1H); 7.6(m, 1H); 7.93(m,         1H); 8.9(m, 1H).                                                              Retention time 3.6 minutes on a reversed phase Partisil 10/25 ODS-2           column, using                                                                 MeOH/H.sub.2 O/TFA, 35:65:0.2, v/v/v as eluant.                               6. The 3-aminomethylcephalosporin may be prepared as follows: To a            stirred suspension of 2-                                                      (2-formamidothiazol-4-yl)-2-oxoacetic acid (6.1 g) in DMF (50 ml) was         added pyridine (2.65 ml)                                                      and 4N aqueous hydrochloric acid (8.52 ml.), followed by dropwise             addition of t-butyl 2-amino-                                                  oxypropionate (5.28 g). After stirring for 18 hours at ambient                temperature, the mixture was                                                  diluted with water, acidified, and worked up in a conventional manner by      extraction into EtOAc.                                                        Crude product was dissolved in a mixture of ether (80 ml) and EtOAc (40       ml), and N-methyl-                                                            morpholine (7.6 ml) added. The precipitate was filtered to give               2-[(Z)-1-(tert-butoxy-                                                        carbonyl)ethoxy-imino]-2-(2-formamidothiazol-4-yl)acetic acid as its          N-methyl-morpholine salt,                                                     having the following n.m.r. in d.sub.6 DMSO: 1.35(d, 3H); 1.41(s, 9H);        2.35(s, 3H); 2.56(t, 4H);                                                     3.65(t, 4H); 4.55(q, 1H); 7.35(s, 1H); 8.46(s, 1H).                           Oxalyl chloride (2.61 ml) and DMF (2.3 ml) were added to CH.sub.2             Cl.sub.2 (100 ml) at -10° C.,                                          and stirred for 30 minutes. The above N-methylmorpholine salt (12.06 g)       was added, followed by                                                        N-methylmorpholine (0.60 ml), and stirring continued for 30 minutes.          Meanwhile, in a separate                                                      flask, a suspension of 7-amino-3-azidomethyl-ceph-3-em-4-carboxylic acid      (7.27 g) in CH.sub.2 Cl.sub.2                                                 (40 ml) was treated with N,O-bis(trimethylsilyl)acetamide (14.1 ml), and      stirred for 1 hour to                                                         give a clear solution, which was transferred by syringe to the acid           chloride solution. After                                                      stirring for 1 hour at -10° C., the temperature was allowed to         come to ambient. The                                                          mixture was poured into water (100 ml) and organics extracted into EtOAc.     Removal of solvent                                                            gave 3-azido-methyl-7-[ 2-((Z)-1-(t-butoxycarbonyl)ethoxyimino)-2-(2-forma    midothiazol-4-yl)-                                                            acetamido]ceph-3-em-4-carboxylic acid, as a mixture of diastereoisomers,      having the following                                                          n.m.r. in solvent A: 1.35(s, 9H); 1.37 and 1.38(2xd, 3H); 3.41(2xd, 1H);      3.61(d, 1H); 3.82(2xd, 1H);                                                   4.34(d, 1H); 4.56(2xq, 1H); 5.14(2xd, 1H); 5.83(d, 1H); 7.32(2xs, 1H);        8.39(s, 1H).                                                                  A solution of the above 3-azidomethyl compound (16.5 g) in a mixture of       isopropanol (110 ml),                                                         water (20 ml) and concentrated hydrochloric acid (7.5 ml) was stirred for     3 days at ambient                                                             temperature. After cooling to 0° C., the pH was raised to 3 using      triethylamine, solvents were                                                  evaporated, the residue treated with water (100 ml.) and organics             extracted into EtOAc. Evapor-                                                 ation gave 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-(t-butoxycarbonyl)ethoxyimi    no)acetamido]-3-                                                              azidomethylceph-3-em-4-carboxylic acid, as a mixture of diastereoisomers,     having the following                                                          n.m.r in solvent A: 1.4 and 1.42(2xc, 3H); 1.44(s, 9H); 3.46(2xd, 1H);        3.66(d, 1H); 3.88(2xd, 1H);                                                   4.39(d, 1H); 4.55(q, 1H); 5.18(d, 1H); 5.84(d, 1H); 6.74(2xs, 1H).            The above deprotected 3-azidomethylcephem (12.2 g) was added to 90% v/v       aqueous TFA (60                                                               ml) pre-cooled to 0° C., and stirred for 30 minutes. Raney nickel      (wet, 2.5 g) was added, and the                                               mixture stirred 20 minutes, allowing the temperatre to rise to ambient.       The mixture was filtered,                                                     solvents evaporated and the residue dissolved in water, and the pH raised     to 3 with sodium                                                              acetate. Careful chromatography on Diaion HP20SS, eluting successively        with water, then                                                              water/CH.sub.3 CN, 97.5:2.5 v/v and water/CH.sub.3 CN 95:5 v/v, allowed       substantial separation of the                                                 two diastereoisomers of 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-    carboxyethoxy-                                                                imino)acetamido]ceph-3-em-4-carboxylic acid. The more polar (m.p.)            isomer, having retention                                                      time 3.05 minutes on a reversed phase Partisil PXS 10/25 ODS-2 column,        using MeOH/H.sub.2 O/                                                         HOAc 20:80:1 v/v/v as eluant, had the following n.m.r. in solvent A:          1.37(d, 3H); 3.23(d, 1H);                                                     3.44(d, 1H); 3.53(d, 1H); 3.65(d, 1H); 4.52(q, 1H); 4.99(d, 1H); 5.8(d,       1H); 6.79(s, 1H).                                                             The less polar (l.p.) isomer, having retention time 4.7 minutes under         identical conditions to the                                                   above, had the following n.m.r. in solvent A: 1.43(d, 3H); 3.2(d, 1H);        3.42(d, 1H); 3.53(d, 1H);                                                     3.64(d, 1H); 4.52(q, 1H); 5.0(d, 1H); 5.72(d, 1H); 6.81(s, 1H).               7. n.m.r. in solvent A: 1.42(d, 3H); 3.45(d, 1H); 3.64(d, 1H); 4.08(d,        1H); 4.24(s, 3H); 4.56(d, 1H);                                                4.63(q, 1H); 5.12(d, 1H); 5.81(d, 1H); 6.79(s, 1H); 7.6(m, 1H); 7.95(m,       1H); 8,95(m, 1H). Retention                                                   time 4.6 min. on a reversed phase Partisil PXS 10/25 ODS-2 column, using      MeOH/H.sub.2 O/TFA,                                                           35:65:0.2 v/v/v, as eluant.                                                   8. n.m.r. in solvent A: 1.38(d, 3H); 3.31(d, 1H); 3.59(d, 1H); 4.27(d,        1H); 4.56(q, 1H); 4.59(d, 1H);                                                5.02(d, 1H); 5.77(d, 1H); 6.78(s, 1H); 7.05(d, 1H); 7.66(d, 1H); 8.1(d,       1H); 8.69(d, 1H). Retention                                                   time 3.3 minutes on a reversed phase Partisil 10/25 ODS0-2 column, using      MeOH/H.sub.2 O/TFA,                                                           40:60:0.2, v/v/v, as eluant.                                                  9. n.m.r. in solvent A: 1.41(d, 3H); 3.36(d, 1H); 3.61(d, 1H); 4.23(d,        1H); 4.6(m, 3H); 5.05(d, 1H);                                                 5.74(d, 1H); 6.8(s, 1H); 7.03(d, 1H); 7.67(d, 1H); 8.11(d, 1H); 8.7(d,        1H). Retention time 4.3                                                       minutes on a reversed phase Partisil 10/25 ODS-2 column, using                MeOH/H.sub.2 O/TFA, 40:60:0.2,                                                v/v/v, as eluant.                                                             10. n.m.r. in solvent A: 2.38(t, 4H); 3.35(d, 1H); 3.62(d, 1H); 4.27(d,       1H); 4.66(d, 1H); 5.06(d, 1H);                                                5.76(d, 1H); 6.76(s, 1H); 7.04(d, 1H); 7.66(d, 1H); 8.1(d, 1H); 8.7(d,        1H).                                                                          11. The basic procedure of Examples 1-4 was used, except the reaction         mixture was heated at                                                         60° C. for 2 hours, and product was isolated by chromatography on      Diaion HP20SS. The starting                                                   heterocycle was 6-amino-3-fluoro-1-methylpyridazinium tetrafluoroborate.      12. n.m.r. in solvent A: 2.33(m, 4H); 3.28(d, 1H); 3.56(d, 1H); 3.65(s,       3H); 3.83(d, 1H); 4.27(d,                                                     1H); 5.0(d, 1H); 5.68(d, 1H); 6.7(s, 1H); 8.23(s, 2H).                        13. n.m.r. in solvent A: 2.66(s, 3H); 3.35(d, 1H); 3.61(d, 1H); 4.08(d,       1H); 4.26(s, 3H); 4.47(s, 2H);                                                4.51(d, 1H); 5.03(d, 1H); 5.72(d, 1H); 6.87(s, 1H); 7.62(m, 1H); 7.94(m,      1H); 8.91(d, 1H).                                                             14. The 3-aminomethylcephalosporin may be prepared as follows: Using the      general procedure of                                                          Footnote 6 above, 2-((Z)-N-methylcarbamoylmethoxyimino)-2-(2-tritylaminoth    iazol-4-yl)acetic                                                             acid was condensed with 7-amino-3-azidomethylceph-3-em-4-carboxylic acid      to give the                                                                   appropriate 7-amido-3-azidomethylcephalosporin. This was then reduced,        with accompanying                                                             removal of the trityl group, by the same general procedure to give            3-aminomethyl-7-[2-(2-amino-                                                  thiazol-4-yl)-2-((Z)-N-methylcarbamoylmethoxyimino)acetamido]ceph-3-em-4-c    arboxylic acid,                                                               used without further characterisation in subsequent stages.                   15. n.m.r. in solvent A: 2.8(s, 3H); 2.92(s, 3H); 3.3(d, 1H); 3.61(d,         1H); 4.06(d, 1H); 4.24(s, 3H);                                                4.49(d, 1H); 4.81(s, 2H); 5.02(d, 1H); 5.71(d, 1H); 6.82(s, 1H); 7.6(m,       1H); 7.93(dd, 1H); 8.89(d,                                                    1H).                                                                          16. The 3-aminomethylcephalosporin may be prepared as follows: Using the      general procedure of                                                          Footnote 6 above, 2-((Z)-N,N-dimethylcarbamoylmethoxyimino)-2-(2-tritylami    nothiazol-4-                                                                  yl)acetic acid was condensed with 7-amino-3-azidomethylceph-3-em-4-carboxy    lic acid, to give                                                             the appropriate 7-amido-3-azidomethylcephalosporin. This was reduced, by      the same general                                                              procedure, to give, after chromatography on Diaion HP20SS resin and           eluting with isopropanol/                                                     water, 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2((Z)-N,N-dimethylcarbamoy    lmethoxy-                                                                     imino)acetamido]ceph-3-em-4-carboxylic acid, used without further             characterisation for                                                          subsequent stages.                                                            17. n.m.r. in solvent A: 3.34(d, 1H); 3.63(d, 1H); 3.94(m, 2H); 4.08(d,       1H); 4.25(s, 3H); 4.55(d,                                                     1H); 4.6(s, 2H); 5.05(d, 1H); 5.74(d, 1H); 6.87(s, 1H); 7.63(m, 1H);          7.94(dd, 1H); 8.92(d, 1H).                                                    18. The starting material may be obtained as follows: 2,2,2-Trifluoroethyl    amine hydrochloride                                                           (27.1 g) was suspended in dichloromethane (300 ml), cooled to 5°,      and triethylamine (55.6 ml)                                                   was run in. A solution of bromoacetyl bromide (18 ml) in dichloromethane      (200 ml) was run in                                                           over the course of 3 hours. After a conventional extractive work-up, the      crude product was                                                             distilled to give N-(2,2,2-trifluoroethyl)-2-bromoacetamide, n.m.r. in        CDCl.sub.3 : 3.93(m, 4H);                                                     6.9(br, 1H).                                                                  Ethyl 2-(Z)-hydroxyimino-2-(2-tritylaminothiazol-4-yl)acetate                 hydrochloride (19.7 g) was                                                    dissolved in DMSO (150 ml), treated with potassium carbonate (15.4 g),        and the above bromo-                                                          acetamide (12.7 g) was added. After stirring for 24 hours, the reaction       mixture was diluted with                                                      water (500 ml) and worked-up by conventional extraction. Product was          purified by chromato-                                                         graphy on silica gel, to give ethyl 2-[(Z)-N-(2,2,2-trifluoroethyl)carbamo    ylmethoxyimino]-2-(2-                                                         tritylaminothiazol-4-yl)acetate, n.m.r. in CDCl.sub.3 : 1.38(t, 3H);          3.94(m, 2H); 4.41(q, 2H), 4.82(s,                                             2H); 6.63(s, 1H); 7.0 (m, 2H); 7.35(m, 15H).                                  The ester was dissolved in methanol, and hydrolysed at ambient                temperature by addition of                                                    aqueous sodium hydroxide. The sodium salt precipitated and was filtered       off. After resuspension                                                       in water and acidification with 2N hydrochloric acid, there was obtained      2-[(Z)-N-(2,2,2-tri-                                                          fluoroethyl)carbamoylmethoxyimino]-2-(2-tritylaminothiazol-4-yl)acetic        acid. Following the                                                           procedure outlined in Footnote 14 above, this was condensed with              7-amino-3-azidomethylceph-3-                                                  em-4-carboxylic acid, and the product was reduced, to give                    3-aminomethyl-7-[2-(2-aminothiazol-                                           4-yl)-2-[(Z)-N-(2,2,2-trifluoroethyl)carbamoylmethoxyimino]acetamido]-ceph    -3-em-4-carboxylic                                                            acid, used without further purification for subsequent stages.                19. Product obtained as a 6:4 mixture of diastereoisomers, n.m.r. in          solvent A: 2.26(m, 2H);                                                       3.22(m, 2H); 3.32(d, 1H); 3.59(d, 1H); 4.06(d, 1H); 4.25(s, 3H); 4.48(d,      1H); 4.68 and 4.74(2xt,                                                       1H); 5.01(d, 1H); 5.66(d, 1H); 6.78 and 6.81(2xs, 1H); 7.61(br. 1H);          7.93(dd, 1H); 8.91(d, 1H).                                                    20. The 3-aminomethylcephalosporin may be prepared as follows: Using the      general procedure                                                             outlined in Footnote 6 above, 2-((Z,RS)-2-oxopyrrolidin-3-yloxy-imino)-2-(    2-tritylaminothiazol-                                                         4-yl)acetic acid was condensed with 7-amino-3-azidomethylceph-3-em-4-carbo    xylic acid to give                                                            3-azidomethyl-7-[2-((Z,RS)-2-oxopyrrolidin-3-yloxyimino)-2-(2-tritylaminot    hiazol-4-                                                                     yl)acetamido]ceph-3-em-4-carboxylic acid, n.m.r. in solvent A: 2.53(m,        2H); 3.3-3.6(m, 4H);                                                          4.09(d, 1H); 4.45(d, 1H); 5.05(m, 2H); 5.88(d, 1H); 6.75(s, 1H); 7.33(m,      15H).                                                                         The azide was reduced by the standard procedure to give                       3-aminomethyl-7-[2-(2-aminothiazol-                                           4-yl)-2((Z,RS)-2-oxopyrrolidin-3-yloxyimino)acetamido]-ceph-3-em-4-carboxy    lic acid as a 6:4                                                             mixture of diastereoisomers, n.m.r. in solvent A: 2.3(m, 2H); 3.1-3.8(m,      6H); 4.73 and 4.78(2xt,                                                       1H); 5.02(d, 1H); 5.72(d, 1H); 6.81 and 6.83(2xs, 1H).                        21. n.m.r. in solvent A: 1.23(t, 3H); 3.32(d, 1H); 3.6(d, 1H); 3.71(s,        3H); 4.05(m, 4H); 5.01(d, 1H);                                                5.68(d, 1H); 6.71(s, 1H); 7.28(s, 2H).                                        22. n.m.r. in solvent A: 0.93(t, 3H); 1.78(quintet, 2H); 3.34(d, 1H);         3.58(d, 1H); 4.06(br, 1H);                                                    4.22(s, 3H); 4.42(t, 1H); 4.46(br, 1H); 5.02(d, 1H); 5.75(d, 1H);             7.59(br, 1H); 7.91(br, 1H); 8.9(d,                                            1H). Retention time 5.8 minutes on a reversed phase Partisil PXS 10/25        ODS-2 column, using                                                           MeOH/water/TFA 40:60:0.2 v/v/v as eluant.                                     23. The 3-aminomethylcephalosporin may be prepared as follows: Hydrazine      hydrate (15 ml) was                                                           added dropwise to a stirred solution of t-butyl 2-(N-phthalimido-oxy)-buty    rate (45.8 g) in                                                              dichloromethane (600 ml) at ambient temperature. After 2 hours, a mixture     of 25% aqueous                                                                ammonia (120 ml) and water (200 ml) was added, and t-butyl-2-aminoxybutyra    te isolated by a                                                              conventional extractive procedure. By following the procedure of Footnote     6, this was                                                                   converted to 2-[(Z)-1-(t-butoxycarbonyl)propoxyimino]-2-(2-formamidothiazo    l-4-yl)-acetic acid,                                                          precipitated as its triethylamine salt, having the following n.m.r. in        d.sub.6 -DMSO: 0.94(t, 3H);                                                   1.21(t, 9H); 1.46(s, 9H); 1.73(quintet, 2H); 3.03(q, 6H); 4.3(t, 1H);         7.25(s, 1H); 8.51(s, 1H).                                                     Following the procedure of Footnote 6, the above acetic acid was              condensed with 7-amino-3-                                                     azido-methylceph-3-em-4-carboxylic acid, the formyl group was removed by      hydrolysis, and the                                                           resulting product was reduced to the 3-aminomethylcephem. Careful             chromatography on Diaion                                                      HP20SS, eluting successively with water, water/CH.sub.3 CN, 97.5:2.5 v/v,     water CH.sub.3 CN, 95:5 v/v                                                   and water/CH.sub.3 CN, 92.5:7.5 v/v, allowed substantial separation of        the diasteroisomers of                                                        3-aminomethyl-7-[2-aminothiazol-4-yl)-2-((Z)-1-carboxy-propoxyimino)acetam    ido]ceph-3-em-4-                                                              carboxylic acid. The more polar (m.p.) isomer, having retention time 3.02     minutes on a reversed                                                         phase Partisil PXS 10/25 ODS-2 column, using MeOH/H.sub.2 O/HOAc 30:70:1      v/v/v as eluant, had                                                          the following n.m.r. in solvent A: 0.95(t, 3H); 1.8(m, 2H); 3.28(d, 1H);      3.43(d, 1H); 3.58(d, 1H);                                                     3.69(d, 1H); 4.45(t, 1H); 5.02(d, 1H); 5.75(d, 1H); 6.79(s, 1H).              The less polar (l.p.) isomer, having retention time 3.76 minutes under        identical conditions to the                                                   above, had the following n.m.r, in solvent A: 1.0(t, 3H); 1.83(m, 2H);        3.28(d, 1H); 3.43(d, 1H);                                                     3.58(d, 1H); 3.69(d, 1H); 4.43(t, 1H); 5.03(d, 1H); 5.71(d, 1H); 6.77(s,      1H).                                                                          24. n.m.r. in solvent A: 0.94(t, 3H); 1.79(quintet, 2H); 3.34(d, 1H);         3.56(d, 1H); 4.05(br, 1H);                                                    4.22(s, 3H); 4.37(t, 1H); 4.47(br, 1H); 5.03(d, 1H); 5.69(d, 1H); 6.77(d,     1H); 7.6(br, 1H); 7.92(br,                                                    1H); 8.9(d, 1H)). Retention time 6.8 minutes on a reversed phase Parisil      PXS 10/25 ODS-2                                                               column, using MeOH/water/TFA 40:60:0.2 v/v/v as eluant.                       25. n.m.r. in solvent A: 1.65(m, 4H); 2.03(m, 4H); 3.34(d, 1H); 3.61(d,       1H); 4.25(d, 1H); 4.65(d,                                                     1H); 5.03(d, 1H); 5.72(d, 1H); 6.75(s, 1H); 7.03(d, 1H); 7.67(d, 1H);         8.1(d, 1H); 8.7(d, 1H).                                                       26. Starting material was 2,3-dihydro-7-methylthiothiazolo[2,3-a]pyrimidin    ium tetrafluoroborate.                                                        27. n.m.r. in solvent A: 1.67(m, 4H); 2.04(m, 4H); 3.27(d, 1H); 3.58(d,       1H); 3.69(t, 2H); 4.22(d,                                                     1H); 4.55(d, 1H); 4.6(t, 2H); 5.04(d, 1H); 5.73(d, 1H); 6.67(d, 1H);          6.75(s, 1H); 8.12(d, 1H).                                                     28. The starting material was prepared by dissolving 1-(2-cyanothiazol-4-y    l)methyl-4-methylthio-                                                        pyridinium chloride (242 mg) in a mixture of dichloromethane (11 ml) and      TFA (2 ml), cooling                                                           in ice, and treating with 3-chloroperoxybenzoic acid (232 mg). After          stirring for 40 minutes                                                       solvents were evaporated and the residue was treated with water (8 ml)        and extracted with ether                                                      (3 portions of 5 ml). The aqueous layer containing 1-(2-cyanothiazol-4-yl)    methyl-4-methyl-                                                              sulphinylpyridinium salts was used as such.                                   29. n.m.r. in solvent A: 1.82(m, 2H); 2.37(t, 4H); 3.29(d, 1H); 3.52(d,       1H); 4.21(d, 1H); 4.41(d,                                                     1H); 5.04(d, 1H); 5.53(s, 2H); 5.72(d, 1H); 6.75(s, 1H); 6.95(dd, 1H);        7.34(dd, 1H); 8.17(dd, 1H);                                                   8.29(s, 1H); 8.34(dd, 1H).                                                    30. The starting material was prepared as in Footnote 28, but starting        from 4-methylthio-1-(1,2,3-                                                   thiadiazol-4-yl)methylpyridinium methanesulphonate.                           31. n.m.r. in solvent A: 1.82(m, 2H); 2.38(t, 4H); 3.28(d, 1H); 3.51(d,       1H); 4.2(d, 1H); 4.41(d, 1H);                                                 5.05(d, 1H); 5.71(d, 1H); 5.82(s, 2H); 6.73(s, 1H); 6.94(dd, 1H);             7.35(dd, 1H); 8.25(d, 1H); 8.43(d,                                            1H); 9.26(s, 1H).                                                             32. n.m.r. in solvent A: 1.41(d, 3H); 3.27(d, 1H); 3.51(d, 1H); 4.21(d,       1H); 4.51(d, 1H); 4.59(q,                                                     1H); 5.06(d, 1H); 5.74(d, 1H); 5.86(s, 2H); 6.76(s, 1H); 6.95(dd, 1H);        7.35(dd, 1H); 8.27(d, 1H);                                                    8.45(d, 1H); 9.27(s, 1H).                                                     Retention time 5.0 minutes on a reversed phase Partisil PXS 10/25 ODS-2       column using MeOH/                                                            water/TFA 35:65:0.2 v/v/v as eluant.                                          33. n.m.r. in solvent A: 0.92(t, 3H); 1.78(quintet, 2H); 3.27(d, 1H);         3.36(d, 1H); 4.21(d, 1H);                                                     4.42(d, 1H); 4.44(t, 1H); 5.04(d, 1H), 5.72(d, 1H); 5.86(s, 2H); 6.76(s,      1H); 6.95(dd, 1H); 7.32(dd,                                                   1H); 8.27(d, 1H); 8.45(d, 1H); 9.26(s, 1H). Retention time 7.6 minutes on     a reversed phase Partisil                                                     PXS 10/25 ODS-2 column, using MeOH/water/TFA 35:65:0.2 v/v/v as eluant.       34. The starting material was prepared as in Footnote 28, but starting        with 1-(E-3-cyano-2-                                                          methylallyl)-4-methylthiopyridinium bromide, and using two equivalents of     3-chloroperoxy-                                                               benxoic acid, to give substantially 1-(E-3-cyano-2-methylallyl)-4-methanes    ulphonylpyridinium                                                            bromide.                                                                      35. n.m.r. in solvent A: 0.95(t, 3H); 1.8(quintet, 2H); 1.96(d, 3H);          3.29(d, 1H); 3.54(d, 1H);                                                     4.24(d, 1H); 4.43(d, 1H); 4.45(t, 1H); 4.93(s, 2H); 5.06(d, 1H); 5.23(d,      1H); 5.74(d, 1H); 6.78(s,                                                     1H); 6.96(dd, 1H); 7.31(dd, 1H); 8.01(dd, 1H); 8.19(dd, 1H).                  Retention time 4.3 minutes on a reversed phase Partisil PXS 10/25 ODS-2       column, using MeOH/                                                           Water/TFA 40:60:0.2 v/v/v as eluant.                                          36. n.m.r. in solvent A: 1.67(br, 4H); 2.0(br, 4H); 3.31(d, 1H); 3.61(d,      1H); 4.24(s + m, 4H);                                                         4.46(d, 1H); 5.01(d, 1H); 5.71(d, 1H); 6.72(s, 1H); 7.6(m, 1H); 7.82(m,       1H); 8.84(d, 1H).                                                         

EXAMPLE 219

The general procedure of Examples 7-14 was repeated using DMF as solventat ambient temperature, with the appropriate starting materials.Products were worked up by chromatography on Diaion CHP20P resin,eluting with CH₃ CN/water mixtures. The following compounds were made.

    ______________________________________                                         ##STR267##                                                                   Example                          Yield Foot-                                  No.    R.sup.1    R.sup.2        %     notes                                  ______________________________________                                        219                                                                                   ##STR268##                                                                               ##STR269##    48    1, 2, 3                                ______________________________________                                        Footnotes                                                                     1. Starting material was 1-methyl-4-methylthiothieno[2,3-                     d]pyrimidinium tetrafuloroborate.                                             2. n.m.r. in solvent A: 1.29(t, 3H); 1.38(d, 3H); 3.21(d, 1H);                3.44(d, 1H); 4.01(s + m, 5H); 4.56(q, 1H); 4.86(d, 1H); 5.05(d,               1H); 5.22(d, 1H); 5.74(d, 1H); 6.75(s, 1H); 7.8(d, 1H); 7.9(d, 1H);           8.81(s, 1H).                                                                  Retention time 5.1 minutes on a reversed phase Partisil PXS 10/25             ODS-2 column, using MeOH/H.sub.2 O/TFA 40:60:0.2 as eluant.                   3. The cephalosporin intermediate may be prepared as follows:                 To a stirred solution of triethylamine (0.18 ml) in MeOH (50 ml)              was added 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-                  carboxyethoxyimino)-acetamido]ceph-3-em-4-carboxylic acid                     (more polar isomer, 0.6 g), followed by sodium cyanoborohydride               (0.08 g). A solution of acetaldehyde (0.07 ml) in MeOH (5 ml)                 was added over 40 minutes, then the solvent was removed and the               residue was dissolved in water (100 ml). After reducing the pH                to 3.5, the solution was loaded onto a column of Diaion CHP20P                resin. Elution with 95:5 H.sub.2 O:CH.sub.3 CN gave 7-[2-(2-amino-            thiazol-4-yl)-2-((Z)-1-carboxyethoxyimino)acetamido]-3-ethyl-                 aminomethylceph-3-em-4-carboxylic acid (more polar isomer),                   having the following n.m.r. in solvent A: 1.19(t, 3H); 1.43(d, 3H);           2.94(q, 2H); 3.37(d, 1H); 3.41(d, 1H); 3.6(d, 1H); 3.76(d, 1H);               4.61(q, 1H); 5.03(d, 1H); 5.75(d, 1H); 6.78(s, 1H).                           Retention time 3.25 minutes on a reversed phase Partisil PXS                  10/25 ODS-2 column, using MeOH/water/HOAc 25:75:1 as                          eluant.                                                                   

EXAMPLE 220

Dry dichloromethane (5 ml) was cooled to -10° and oxalyl chloride (1.15mM), followed by DMF (1.15 mM), was added, and the mixture was stirredat -15° to -10° for 1 hour. To this was then added1-(Z)-chloroethylene-2-(2-formamidothiazol-4-yl)acetic acid (1 mM),followed by N-methylmorpholine (1.15 mM), and the mixture was stirredfor 1 hour at -15° to -10°.

In another flask a solution of7-amino-3-(1-methyl-4-pyridinio)aminomethylceph-3-em-4-carboxylic acid(1.15 mM), as its partial salt with 1.76 moles TFA, in dimethylacetamide(6 ml) was treated with N-methylmorpholine (2.08 mM), and the pinksuspension was syringed into the flask containing the activated acid, isfollowed by N-methylmorpholine (1.15 mM). After stirring for 1 hour, at-10° and 1 hour at ambient temperature, the mixture was filtered. Thesolution was evaporated to dryness, and deformylated by solution inmethanol (20 ml) and treating with concentrated hydrochloric acid (0.5ml), at ambient temperature for 2 hours. After removal of the methanol,the residue was dissolved in water, the pH was adjusted to 5.2 withaqueous NaHCO₃, and the product was purified by chromatography on DiaionCHP20P resin to give7-[2-(2-aminothiazol-4-yl)-2-(Z)-chloromethyleneacetamido]-3-(1-methyl-4-pyridinio)aminomethylceph-3-em-4-carboxylicacid, in 5% yield, having the following n.m.r. in solvent A: 3.27 (d,1H); 3.5 (d, 1H); 3.84 (s, 3H); 4.19 (d, 1H); 4.41 (d, 1H); 5.07 (d,1H); 5.66 (d, 1H); 6.38 (s, 1H); 6.82 (s, 1H); 6.89 (d, 1H); 7.26 (d,1H); 8.01 (d, 1H); 8.18 (d, 1H).

EXAMPLES 221-228

To a stirred suspension of3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylicacid (240 mg, 0.5 mmole) and triethylamine (200 ul, 1.4 mmole) in EtOH(10 ml) at 25° was added 1-methyl-4-methylthioquinazolinium iodide (160mg. 0.5 mmole). After 1.5 hours the solution was evaporated to drynessunder reduced pressure, the residue dissolved in water (10 ml), thesolution acidified with excess 5% v/v aqueous HOAc and the insolublematerial filtered off. The filtrate was applied to a Dianion HP20 columnand the product purified by gradient elution with MeOH. Using thisgeneral process and the appropriate quaternary heterocycle, thefollowing compounds were obtained:

    __________________________________________________________________________     ##STR270##                                                                   Example                            Yield                                      No.  R.sub.1      R.sub.2                                                                          R.sub.3                                                                          R.sub.4    %   Footnotes                              __________________________________________________________________________    221  CH.sub.3     CH.sub.3                                                                         CH.sub.3                                                                         H          11  1, 2, 3                                222  CH.sub.3     H  H  H           9  4, 5, 6                                223  CH.sub.2 CHCH.sub.2                                                                        H  H  H          44  7, 8, 6                                224                                                                                 ##STR271##  H  H  H          33  9, 10, 6                               225  CH.sub.3     H  H  CH.sub.2 CH.sub.3                                                                        29  11, 12, 13,                                                                   5, 6                                   226  CH.sub.2 CHCH.sub.2                                                                        H  H  CH.sub.2 CH.sub.3                                                                        22  14, 15, 13,                                                                   8, 6                                   227  CH.sub.2 CHCH.sub.2                                                                        H  H                                                                                 ##STR272##                                                                              46  16, 17, 18, 19, 8, 6                   228  CH.sub.3     H  H                                                                                 ##STR273##                                                                              35  20, 21, 22, 5, 6                       __________________________________________________________________________    Footnotes                                                                     1. n.m.r. in solvent A: 1.41(s, 3H); 1.43(s, 3H); 2.52(m, 6H); 3.49(d,        1H); 3.72(d, 1H); 3.94(s,                                                     3H); 4.26(d, 1H); 4.82(d, 1H); 5.02(d, 1H); 5.76(d, 1H); 6.75(s, 1H);         8.74(s, 1H).                                                                  2. The 1,5,6-trimethyl-4-methylthiothieno[2,3-d]pyrimidinium iodide may       be prepared as                                                                follows: A solution of 5,6-dimethyl-4-methylthiothieno[2,3-d]pyrimidine       in CH.sub.2 Cl.sub.2 was                                                      treated with trimethyloxonium tetrafluoroborate and stirred, under argon,     at room tempera-                                                              ture overnight. The solution was evaporated to dryness to give a white        solid. N.mr. in d.sub.6                                                       DMSO: 2.6(s, 6H); 2.8(s, 3H); 4.2(s, 3H); 9.4(s, 1H).                         3. 5,6-Dimethyl-4-methylthiothieno[2,3-d]-pyrimidine may be prepared as       follows: A solution                                                           of 5,6-dimethyl-1H-thieno[2,3-d]pyrimidin-4-one in CH.sub.3 CN was            treated, at reflux for 3 hr,                                                  with Lawesson's reagent. The reaction mixture was poured into water and       extracted with                                                                ethyl acetate. The organic extracts were combined and extracted several       times with 2N                                                                 NaOH. The aqueous extracts were acidified with HCl and re-extracted with      ethyl acetate,                                                                the extracts washed with water, dried and evaporated to dryness. The          crude 5,6-dimethyl-                                                           1H-thieno[2,3-d]pyrimidin-4-thione so obtained (M.sup.+  = 196) was           alkylated with                                                                methyl iodide in aqueous sodium hydroxide to give, after chromatography       on silica, 5,6-                                                               dimethyl-4-methylthiothieno[2,3-d]pyrimidine. n.m.r. in CDCl.sub.3 :          2.5(s, 6H); 2.6(s,                                                            3H); 8.7(s, 1H). This product was quaternised by heating with excess          methyl iodide under                                                           reflux for 18 hours.                                                          4. n.m.r. in solvent A: 1.4(s, 3H); 1.44(s, 3H); 3.46(d, 1H); 3.62(d,         1H); 4.02(s, 3H); 4.55(d,                                                     1H); 4.9(d, 1H); 5.02(d, 1H); 5.82(d, 1H); 6.72(s, 1H); 7.90(s, 1H);          8.85(s, 1H).                                                                  5. The 1-methyl-4-methylthiothieno[2,3-d]pyrimidinium tetrafluoroborate       was prepared from 4-                                                          methylthiothieno[2,3-d]pyrimidine and trimethyloxonium tetrafluoroborate      by a procedure                                                                analogous to that described in footnote 2. n.m.r. in d.sub.6 DMSO: 2.9(s,     3H); 4.34(s, 3H); 7.88(d,                                                     1H); 8.28(d, 1H); 9.52(s, 1H).                                                6. The 4-methylthiothieno[2,3-d]pyrimidine was prepared from                  1H-thieno[2,3-d]pyrimidine-4-one                                              by a two-stage procedure analogous to that described in footnote 3.           n.m.r. in CDCL.sub.3 : 2.72                                                   (s, 3H); 7.35(d, 1H); 7.45(d, 1H); 8.85(s, 1H).                               7. n.m.r. in solvent A: 1.36(s, 3H); 1.38(s, 3H); 3.36(d, 1H); 3.6(d,         1H); 4.56(d, 1H); 4.88(d,                                                     1H); 5.04(d, 3H); 5.42(d, 1H); 5.48(d, 1H); 5.75(d, 1H); 6.04(m, 1H);         6.75(s, 1H); 7.86(d,                                                          1H); 7.93(d, 1H); 8.92(s, 1H).                                                8. The 1-allyl-4-methylthiothieno[2,3-d]pyrimidinium bromide was prepared     from 4-methylthio-                                                            thieno[2,3-d]pyrimidine and allyl bromide in refluxing acetonitrile. The      excess allyl bromide                                                          and solvent were removed by evaporation. n.m.r. in d.sub.6 DMSO: 2.9(s,       3H); 5.45(d, 2H);                                                             5.6(d, 1H); 5.75(d, 1H); 6.18(m, 1H); 7.88(d, 1H); 8.32(d, 1H); 9.72(s,       1H).                                                                          9. n.m.r. in solvent A: 1.42(s, 3H); 1.44(s, 3H); 3.40(d, 1H); 3.62(d,        1H); 4.6(d, 1H); 4.92(d,                                                      1H); 5.08(d, 1H); 5.76(d, 1H); 5.84(s, 2H); 6.74(s, 1H); 7.75(d, 1H);         7.8(d, 1H); 7.92(d, 1H);                                                      8.24(d, 1H); 9.18(s, 1H).                                                     10. The 4-methylthio-1-p-nitrobenzylthieno[2,3-d]-pyrimidinium bromide        was prepared as                                                               follows: 4-Methyl-thiothieno[2,3-d]pyrimidine in CH.sub.3 CN was treated      with p-nitrobenzyl                                                            bromide and the solution refluxed for 8 hr. The solution was evaporated       to dryness and the                                                            residue triturated with CH.sub.2 Cl.sub.2. The insoluble solid was            filtered off, and                                                             dried. n.m.r. in d.sub.6 DMSO: 2.94(s, 3H); 6.16(s, 2H); 7.82(dd, 2H);        8.2(d, 1H); 8.25(d, 1H);                                                      9.8(s, 1H).                                                                   11. To a stirred suspension of 3-ethylaminoethyl-7-[2-(2-aminothiazol-4-yl    )-2-(( .sub.-- Z)-1-carboxy-1-                                                methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid (260 mg. 0.5 mM)      in DMF                                                                        (5 ml) was added Et.sub.3 N (150 μl, 1.1 mM) followed by                   1-methyl-4-methylthiothieno[2,3-d]-                                           pyrimidinium tetrafluoroborate (150 mg, 0.53 mM). The mixture was stirred     at room temper-                                                               ature overnight before being poured into H.sub.2 O (100 ml). The pH of        the solution was adjusted                                                     to 3.5 with glacial acetic acid and the solution applied to a Diaion          HP20SS column. The                                                            product was eluted using H.sub.2 O and CH.sub.3 CN and the appropriate        fractions were freeze-dried.                                                  12. n.m.r. in solvent A: 1.35(br t, 3H); 1.43(s, 3H); 1.44(s, 3H);            3.38(d, 1H); 3.54(d, 1H); 4.06                                                (m, 2H); 4.06(s, 3H); 4.79(d, 1H); 5.16(d, 1H); 5.28(d, 1H); 5.85(d, 1H);     6.71(s, 1H); 7.82(d,                                                          1H); 7.95(d, 1H); 8.85(s, 1H).                                                13. The 3-ethylaminomethyl-7-[2-(2-aminothiazol-4-yl)-2-(( .sub.--            Z)-1-carboxy-1-methylethoxyimino)-                                            acetamido]ceph-3-em-4-carboxylic acid was prepared as follows:                3-Aminomethyl-7-[2-                                                           (2-aminothiazol-4-yl)-2-(( .sub.-- Z)-1-carboxy-1-methylethoxyimino)acetam    ido]cep-3-em-                                                                 4-carboxylic acid (2 g, 4 mM) was suspended in MeOH (200 ml), and             Et.sub.3 N (570 μl,                                                        4.1 mM) followed by sodium cyanoborohydride were added. The mixture was       stirred,                                                                      under argon, at room temperature and treated, dropwise, during 40 min.        with a solution                                                               of acetaldehyde (276 μl, 4.9 mM) in methanol (2 ml). After 3 hr. the       methanol was                                                                  evaporated under reduced pressure and the product was purified by             chromatography on                                                             Diaion HP20SS using H.sub.2 O and CH.sub.3 CN in a graded elution. The        appropriate                                                                   fractions were combined and freeze dried. N.m.r. in solvent A: 1.15(t,        3H); 1.44(s, 3H);                                                             1.46(s, 3H); 2.82(q, 2H); 3.36(d, 1H); 3.45(d, 1H); 3.59(d, 1H); 3.76(d,      1H); 5.0(d, 1H);                                                              5.77(d, 1H); 6.74(s, 1H).                                                     14. The procedure described in Footnote 11 was followed, but starting         with 1-allyl-4-                                                               methylthiothien-[2,3-d]pyrimidinium bromide.                                  15. n.m.r. in solvent A: 1.32(t, 3H); 1.45(br s, 6H), 3.24(d, 1H);            3.46(d, 1H); 4.10(m,                                                          2H); 4.91(d, 1H); 5.08(d, 1H); 5.26(d, 1H); 5.45(d, 1H); 5.52(d, 1H);         5.72(d, 1H);                                                                  6.05(m, 1H); 6.7(s, 1H); 7.79(d, 1H); 7.92(d, 1H); 8.89(s, 1H).               16. The procedure described in Footnote 11 was followed, but starting         with 3-(2-fluoro-1 .sub.-- H-                                                 imidazol-4-ylmethyl)aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-(( .sub.--       Z)-1-carboxy-1-                                                               methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid and                   1-allyl-4-methylthio-                                                         thieno[2,3-d]pyrimidinium bromide.                                            17. n.m.r. in solvent A: 1.42(s, 3H); 1.46(s, 3H); 3.12(d, 1H); 3.37(d,       1H); 4.93(d, 1H);                                                             4.97(d, 1H); 5.0-5.1(m, 4H); 5.18(d, 1H); 5.44(d, 1H); 5.5(d, 1H);            5.72(d, 1H); 6.02                                                             (m, 1H); 6.72(s, 1H); 6.82(s, 1H); 7.79(d, 1H); 8.04(d, 1H); 8.87(s,          1H).                                                                          18. 3-(2-Fluoro-1H-imidazol-4-ylmethyl)aminomethyl-7-[2-(2-aminothiazol-4-    yl)-2-(( .sub.-- Z)-1-                                                        carboxy-1-methylethoxyimino)-acetamido]ceph-3-em-4-carboxylic acid was        prepared from                                                                 3-(2-fluoro-1-triphenylmethylimidazol-4-ylmethyl)aminomethyl-7-[2-(2-amino    thiazol-4-yl)-2-                                                              (( .sub.-- Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxyl    ic acid by treatment in                                                       CH.sub.2 Cl.sub.2 at room temperature with p-toluene sulphonic acid           H.sub.2 O. The                                                                reaction mixture was poured into water and the aqueous layer applied to a     Diaion HP20SS                                                                 column. The product was obtained by gradient elution with CH.sub.3            CN/H.sub.2 O and freeze-                                                      drying the appropriate fractions. N.m.r. in solvent A: 1.45(br s, 6H);        3.42(d, 1H); 3.54(d,                                                          1H); 3.68(d, 1H); 3.83(d, 1H); 3.92(s, 2H); 5.03(d, 1H); 5.75(d, 1H);         6.76(s, 1H); 6.93(s, 1H).                                                     19. The 3-(2-fluoro-1-triphenylmethylimidazol-4-ylmethyl)aminomethyl-7-[2-    (2-aminothiazol-4-                                                            yl)-2-(( .sub.-- Z)-1-carboxy-1-methylethoxyimino)-acetamido]ceph-3-em-4-c    arboxylic                                                                     acid was prepared from 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((          .sub.-- Z)-1-carboxy-                                                         1-methylethoxy imino)acetamido]ceph-3-em-4-carboxylic acid and                2-fluoro-4-formyl-1-triphenyl-                                                methylimidazole by a procedure analogous to that described in footnote        N.m.r. in solvent A: 1.44(s, 3H); 1.46(s, 3H); 3.32(d, 1H); 3.4(d, 1H);       3.58(d, 1H); 3.75(d,                                                          1H); 3.92(s, 2H); 5.0(d, 1H); 5.71(d, 1H); 6.75(s, 1H); 6.8(s, 1H);           7.13(d, 6H); 7.43(m, 9H).                                                     20. The procedure described in Footnote 11 was followed but starting with     3-(pyrid-3-ylmethyl)                                                          aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-(( .sub.-- Z)-1-carboxy-1-methyle    thoxyimino)acetamido]-                                                        ceph-3-em-4-carboxylic acid.                                                  21. N.m.r. in solvent A: 1.42(s, 6H); 3.35(br d, 1H); 3.54(br d, 1H);         4.04(s, 3H); 5.02(d, 1H);                                                     5.05-5.55(m, 4H); 5.74(d, 1H); 6.72(s, 1H); 7.35(m, 1H); 7.79(br d, 1H);      7.92(m, 2H); 8.48                                                             (br s, 1H); 8.93(s, 1H).                                                      22. 3-(Pyrid-3-ylmethyl)aminomethyl-7-[2-(2-aminothiazol-4-yl)-2((            .sub.-- Z)-1-carboxy-1-                                                       methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid was prepared          following the                                                                 procedure described in Footnote 3, but with 3-formylpyridine as the           aldehyde. N.m.r. in                                                           solvent A: 1.4(s, 3H); 1.44(s, 3H); 3.39(d, 1H); 3.48(d, 1H); 3.65(d,         1H); 3.73(d, 1H); 4.12(s,                                                     2H); 5.02(d, 1H); 5.76(d, 1H); 6.76(s, 1H); 7.38(m, 1H); 7.87(d, 1H);         8.54(br s, 1H); 8.62(s,                                                       1H).                                                                      

EXAMPLES 229-233

To a stirred suspension of the appropriate3-aminomethylceph-3-em-4-carboxylic acid (0.82 mmole) and triethylamine(1.8 mmole) in DMF (10 ml) at 25° was added the appropriate6-chloro-1,2,4-triazolo[4,3-b]-pyridazinium iodide (0.84 mmole). Afterstirring overnight, the mixture was poured into water (100 ml), the pHadjusted to 3.5 with glacial acetic acid and the solution filtered. Thefiltrate was applied to a Diaion HP20P resin column, and the product wasobtained by gradient elution using water and acetonitrile. Theappropriate fractions were freeze-dried.

    __________________________________________________________________________     ##STR274##                                                                   Example                 Yield                                                 No.      R.sub.1                                                                           R.sub.2                                                                             R.sub.3                                                                            %       Footnotes                                     __________________________________________________________________________    229      2-CH.sub.3                                                                        H     H     8      1, 2                                          230      1-CH.sub.3                                                                        H     H    21      3, 4                                          231      1-CH.sub.3                                                                        Cl    H    16      5, 6                                          232      1-CH.sub.3                                                                        H     CH.sub.2 CH.sub.3                                                                  12      7, 8, 4                                       233                             9, 10, 11                                      ##STR275##                                                                   __________________________________________________________________________    Footnotes                                                                     1. n.m.r. in solvent A: 1.46(br s, 6H); 3.42(d, 1H); 3.65(d, 1H);             4.0-4.2(br s, 4H);                                                            4.3-4.5(br s, 1H); 5.04(d, 1H); 5.75(d, 1H); 6.74(s, 1H); 7.3(d, 1H);         8.04(d, 1H);                                                                  approximately 11.0(s, 1H).                                                    2. The triazolopyridazinium salt may be prepared as follows:                  6-chloro-1,2,4-triazolo-                                                      [4,3-b]pyridazine in methanol was treated with methyl iodide, and the         solution was refluxed for 2 hr. Anhydrous ether was then added to the         reaction mixture                                                              and the precipitated solid so obtained was filtered off, washed with a        little ether and                                                              dried under vacuum, m. pt. 238-40°.                                    3. n.m.r. in solvent A: 1.42(s, 3H); 1.45(s, 3H); 3.38(d, 1H); 3.64(d,        1H); 4.1(br s,                                                                4H); 4.38(m, 1H); 5.02(d, 1H); 5.73(d, 1H); 6.74(s, 1H); 7.53(bs, 1H);        8.35(d, 1H);                                                                  9.65(s, 1H).                                                                  4. The 6-chloro-1-methyl-1,2,4-triazolo[4,3-b]pyridazinium iodide may be      prepared                                                                      as follows: 6-chloro-1,2,4-triazolo[4,3-b]pyridazine and methyl iodide        were refluxed                                                                 in acetonitrile for 4 hr. The reaction mixture was cooled and the solid       which had                                                                     precipitated during the reaction was filtered off, washed with a little       acetonitrile, and                                                             dried, m pt 208-210°.                                                  5. n.m.r. in solvent A: 1.42(s, 3H); 1.44(s, 3H); 3.45(d, 1H); 3.66(d,        1H); 4.1(m, 4H);                                                              4.5(d, 1H); 5.04(d, 1H); 5.78(d, 1H); 6.74(s, 1H); 7.57(m, 1H); 8.34(d,       1H).                                                                          6. The 3,6-dichloro-1-methyl-1,2,4-triazolo[4,3-b]pyridazinium iodide was     prepared                                                                      from 3,6-dichloro-1,2,4-triazolo[4,3-b]pyridazine and methyl iodide in        acetonitrile.                                                                 N.m.r. in d.sub.6 DMSO: 4.38(s, 3H); 8.45(d, 1H); 9.12(d, 1H).                7. Prepared from 3-ethylaminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((           .sub.-- Z)-1-carboxy-1-                                                       methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid.                      8. n.m.r. in solvent A: 1.14(t, 3H); 1.42(s, 6H); 3.2(d, 1H); 3.46(d,         1H); 3.6(m, 1H);                                                              3.75(m, 1H); 4.18(s, 3H); 4.64(m, 2H); 5.06(d, 1H); 5.7(d, 1H); 6.72(s,       1H); 8.2(br s,                                                                1H); 8.52(d, 1H); 9.69(s, 1H).                                                9. Sodium hydrogen carbonate was used in place of triethylamine. Yield        3%.                                                                           10. n.m.r. in solvent A: 1.42(s, 3H); 1.45(s, 3H); 3.42(d, 1H); 3.65(d,       1H); 4.07(s, 3H);                                                             4.24(d, 1H); 4.46(d, 1H); 5.01(d, 1H); 5.72(d, 1H); 6.74(s, 1H); 7.82(d,      1H); 7.87(d,                                                                  1H); 8.64(dd, 1H); 8.91(dd, 1H).                                              11. The 3-chloro-1-methyl-1,2,4-triazolo[4,3-b]pyradizinium iodide was        prepared                                                                      from 3-chloro-1,2,4-triazolo[4,3-b]pyridazine and methyl iodide in            acetonitrile.                                                                 The product which separated from solution was filtered off washed with a      little                                                                        CH.sub.3 CN and ether and dried, m. pt. 225-227°.                  

EXAMPLE 234

The process described in Example 221 was repeated using the appropriate3-ethylaminomethyl cephem and quaternary heterocycle to give thefollowing compound:

    __________________________________________________________________________     ##STR276##                                                                   Example No. R        Yield %   Footnotes                                      __________________________________________________________________________    234                                                                                        ##STR277##                                                                            44        1, 2, 3                                        __________________________________________________________________________    Footnotes                                                                     1. n.m.r. in solvent A: 1.34(m, 3H); 1.42(br s, 6H); 2.08(s, 3H); 3.38(d,     1H);                                                                          3.53(d, 1H); 4.02(m, 2H); 4.80(d, 1H); 5.14(d, 1H); 5.2-5.45(overlapping      s, d, 3H); 5.68(s, 1H); 5.84(d, 1H); 6.7(s, 1H); 7.79(d, 1H); 7.9(d, 1H);     8.84(s, 1H).                                                                  2. The chemical shifts quoted probably refer to the major E isomer, but       there is also                                                                 evidence of the minor Z in the n.m.r. spectrum.                               3. The starting material was prepared from 4-methylthiothieno[2,3-d]pyrimi    dine and                                                                      2-bromomethyl-1-cyanoprop-1-ene (mixture of E and Z isomers in the ratio      9:1)                                                                          in CH.sub.3 CN. The precipitate was filtered off and washed with CH.sub.3     CN and dried.                                                                 N.m.r. in d.sub.6 DSMO: 2.1(s, 3H); 2.92(s, 3H); 5.64(s, 2H); 5.86(s,         1H); 7.86(d, 1H);                                                             8.24(d, 1H); 9.6(s, 1H).                                                  

EXAMPLE 235 ##STR278##

3-Aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylicacid (242mg, 0.5 mmole) was suspended in DMF (3 ml) and water (1 ml) andtreated with 2-methylthio-1,2,4-thiadiazolo[2,3-a]pyridinium bromide(132 mg, 0.5 mmole) and then with sodium hydrogen carbonate (240 mg, 2.5mmole) suspended in water (0.5 ml). The solution was stirred at roomtemperature overnight before being diluted with water (25 ml) andapplied to a Diaion HP20SS column. Following gradient elution withacetonitrile/water the product was obtained by freeze-drying theappropriate fractions. Yield 11%. N.m.r. in solvent A: 1.45 (s, 3H);1.46 (s, 3H), 3.64 (d, 1H); 3.76 (d, 1H); 4.34 (d, 1H); 4.88 (d, 1H);5.07 (d, 1H); 5.78 (d, 1H); 6.73 (s, 1H); 7.0 (m, 1H); 7.13 (d, 1H);7.72 (m, 1H); 8.17 (dd, 1H).

EXAMPLES 236-243

A solution of3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamidolceph-3-em-4-carboxylicacid (0.5 mm) and NaHCO₃ (2.5 mM) in water (5 ml) was treated with anappropriate chloro- or methylsulphinyl-substituted quaternaryheterocycle, at room temperature for 18 hrs. The solution was acidifiedwith HOAC and sufficient sodium acetate added to redissolve anyprecipitate. The product was isolated by chromatography on an HP20gravity column, eluting with CH₃ CN/H₂ O mixtures and then freeze-dryingthe appropriate fractions. The following compounds were obtained:

    ______________________________________                                         ##STR279##                                                                   Example                   Yield                                               No.    R                  %        Footnotes                                  ______________________________________                                        236                                                                                   ##STR280##        34       1, 2                                       237                                                                                   ##STR281##        36       3, 4                                       238                                                                                   ##STR282##        27       5, 6                                       239                                                                                   ##STR283##        26       7, 8                                       240                                                                                   ##STR284##        33       9, 10                                      241                                                                                   ##STR285##        57       11, 12                                     242                                                                                   ##STR286##        48       13, 14                                     243                                                                                   ##STR287##        16       15, 16                                     ______________________________________                                        Footnotes                                                                     1. n.m.r. in solvent A: 1.45(2xs, 6H); 3.4(q, 2H); 4.3(q. 2H);                5.05(d, 1H); 5.45(s, 2H); 5.7(d, 1H); 6.7(s, 1H); 6.9-8.5(6xm, 8H).           2. The starting pyridinium salt was obtained by adding 4-hydroxy-             pyridine (10 mM) to a stirred suspension of hexane-washed sodium              hydride (10 mM) in DMF (15 ml). To this solution was added a                  solution of 4-chloromethylpyridine (10 M) in ether (5 ml), (ob-               tained by treating the corresponding 4-chloromethylpyridine                   hydrochloride with NaHCO.sub.3 in aqueous solution, extracting                with ether and drying), and the mixture was stirred at room                   temperature for 18 hrs. The solvents were evaporated, and the                 residue was purified by MPLC, on Merck silica gel 9385, eluting               with MeOH/CH.sub.2 Cl.sub.2, 8-10:92-90, to give 1-(2-pyridylmethyl)-         pyrid-4-one. Yield 65%. N.m.r. in CDCl.sub.3 : 5.0(s, 2H); 7.2-7.8(m,         4H); 6.35(d, 2H); 8.6 (d, 2H). This pyridone (1.5 mM) and tosyl               chloride (1.65 mM) were heated in DMF at 80° for 45 minutes,           the solvent was evaporated, and the residue triturated with                   CH.sub.2 Cl.sub.2 to give 4-chloro-1-(2-pyridylmethyl)pyridinium              tosylate                                                                      in 70% yield. N.m.r. in d.sub.6 DMSO: 2.3(s, 3H); 6.0(s, 2H); 7.1(d,          2H); 7.5(d, 2H); 7.4-8.6(m, 6H); 9.15(d, 2H).                                 3. N.m.r. in solvent A: 1.45(2xs, 6H); 3.4(q, 2H), 4.3(q, 2H); 5.1(d,         1H); 5.35(s, 2H); 5.8(d, 1H); 6.75(s, 1H); 6.95(q, 1H); 7.1(q, 1H);           7.4(d, 2H); 8.2(d, 1H); 8.3(d, 2H); 8.4(d, 1H).                               4. The starting pyridinium salt was obtained as follows: A solution           of 4-chloromethyl-1-oxidopyridinium chloride (5 mM) in ether was              basified with NaHCO.sub.3 solution. The ether solution was separated          and dried, 4-methylthiopyridine was added, the solvent was                    evaporated and the residue was kept at room temperature for 18                hrs. Trituration gave 4-methylthio-1-(1-oxido-pyrid-4-ylmethyl)py-            ridinium chloride. N.m.r. in d.sub.6 DMSO: 2.7(s, 3H); 5.75(s, 2H);           7.6(d, 2H); 8.0(d, 2H); 8.25(d, 2H); 9.05(d, 2H). This thiomethyl             compound (2 mM) was suspended in CH.sub.2 Cl.sub.2 (10 ml) at 0°,      and                                                                           sufficient TFA was added to give a solution. A solution of                    MCPBA (2 mM) in CH.sub.2 Cl.sub.2 (3 ml) was added, and the solution          was allowed to warm to room temperature, then stirred for 1 hr.               The solvents were evaporated, and the residue was triturated                  several times with ether, to remove excess MCPBA, to give 4-                  methylsulphinyl-1-(1-oxidopyrid-4-ylmethyl)-pyridinium chloride,              which was used without further purification or characterisation.              5. N.m.r. in solvent A: 1.4(2xs, 6H); 3.35(q, 2H), 4.3(q, 2H);                5.05(d, 1H); 5.45(s, 2H); 5.7(d, 1H); 6.7(s, 1H); 6.5-8.4(6xm, 8H).           6. The starting pyridinium salt was prepared by the process of                Footnote 4, except that the reactants were warmed together to                 form a homogeneous melt, then heated at 100° for 15 minutes,           cooled and triturated with CH.sub.2 Cl.sub.2. N.m.r. in d.sub.6 DMSO:         2.7(s,                                                                        3H); 5.9(s, 2H); 7.5, 7.95 and 8.35(m, 6H); 8.95(d, 2H). The                  methylthio compound was then oxidised to the required methyl-                 sulphinyl compound as described in Footnote 4.                                7. Reaction solvent was H.sub.2 O/CH.sub.2 CN, (4:1), N.m.r. in solvent       A:                                                                            1.45(2xs, 6H); 3.4(q, 2H), 4.3(q, 2H); 5.05(d, 1H); 5.4(s, 2H); 5.7(d,        1H); 6.7(s, 1H), 6.95(q, 1H); 7.4(q, 1H); 7.55(s, 2H); 8.15(q, 1H);           8.35(q, 1H).                                                                  8. The starting pyridinium salt was prepared by the process of                Footnote 4, from 4-bromomethyl-2,6-dichloropyridine, except that              this starting material reacted exothermically with 4-methylthio-              pyridine, so the reaction mixture was kept below 40° until the         reaction was largely complete, then heated at 100° for 5 minutes.      The product was crystallised form HCl/EtOH. N.m.r. in d.sub.6                 DMSO: 2.75(t, 3H); 5.95(s, 2H); 7.75(s, 2H); 7.95(d, 2H); 9.05(d,             2H). The methylthio compound was oxidised to the required                     methylsulphinyl compound as in Footnote 4. N.m.r. in d.sub.6 -DMSO/           CDCl.sub.3 : 2.95(s, 3H); 5.95(s, 2H); 7.7(s, 2H); 8.4(d, 2H); 9.3(d,         2H).                                                                          9. N.m.r. in solvent A: 1.4(2xs, 6H); 2.25(s, 3H); 3.4(q, 2H); 4.3(q,         2H); 5.05(d, 1H); 5.3(s, 2H); 5.7(d, 1H); 6.7(s, H); 6.9(d, 1H);              7.25(d), 8.05(d, 1H); 8.8(d, 1H).                                             10. The starting pyridinium salt was obtained as follows:                     5-Hydroxymethyl-6-methyluracil (15 mM) was suspended in                       glacial acetic acid (10 ml) and the mixture was saturated with HCl            gas, then heated under reflux for 1/2 hour until the solid material           was dissolved, and filtered. On cooling, 5-chloromethyl-6-methyl-             uracil was obtained, n.m.r. in d.sub.6 DMSO: 2.15(s, 3H); 4.45(s, 2H).        This compound was treated with a solution of 4-methylthio-                    pyridine in CH.sub.2 Cl.sub.2, the solvent was evaporated, and the            residue                                                                       was heated at 100° for 10 minutes. It stayed solid throughout,         but                                                                           formed the required quaternary salt. Yield 93%. N.m.r. in d.sub.6             DMSO: 2.25(s, 3H); 2.65(s, 3H); 5.3(s, 2H); 7.8(d, 2H); 8.7(d, 2H).           This material was oxidised to the required 4-methylsulphinyl start-           ing material, as in Footnote 4.                                               11. N.m.r. in solvent A: 1.45(2xs, 6H); 2.1(s, 3H); 2.45(s, 3H);              3.4(q, 2H); 4.3(q, 2H); 5.0(d, 1H); 5.2(s, 2H); 5.7(d, 1H); 6.75(s,           1H); 6.9(q, 1H); 7.3(q, 1H); 8.0(q, 1H); 8.25(q, 1H).                         12. The starting pyridinium salt was obtained by the process of               Footnote 4. N.m.r. of 4-methylthiopyridinium salt, in d.sub.6 DMSO:           2.15(s, 3H); 2.5(s), 2.7(s, 3H); 5.75(s, 2H); 7.95(d, 2H); 8.85(d, 2H).       The compound was oxidised to the required 4-methylsulphinyl                   starting material as in Footnote 4.                                           13. n.m.r. in solvent A: 0.8-1.0(m, 4H); 1.45(2xs, 6H); 1.9(partially         obscured by solvent peaks); 3.4(q, 2H); 4.3(q, 2H); 5.0(s, 2H);               5.05(d, 1H); 5.7(d, 1H); 6.0(s, 1H); 6.7(s, 1H); 6.9(d, 1H); 7.15(d,          1H); 8.0(d, 1H); 8.15(d, 1H).                                                 14. The starting pyridinium salt was obtained as follows: 6-Chloro-           methyl-2-cyclopropyl-4-hydroxypyridine (10 mM) and 4-methyl-                  thiopyridine (10 mM) were thoroughly mixed and heated at 100°          for 1/2 hour. The mixture partly melted, then re-solidified. On               cooling, the product was triturated with CH.sub.2 Cl.sub.2 to give the        4-methylthiopyridinium salt. Yield 73%. N.m.r. in d.sub.6 DMSO                0.6-1.1(m, 4H); 2.0(m, 1H); 2.7(s, 3H); 5.55(s, 2H); 6.2(s, 1H);              7.95(d, 2H); 8.7(d, 2H). This product was oxidised to the required            4-methylsulphinyl pyridinium salt, as in Footnote 4.                          15. N.m.r. in solvent A: 1.4(s, 6H); 3.1(s, 3H); 3.4(q, 2H); 4.3(q,           2H); 5.05(d, 1H); 5.3(s, 2H); 5.75(d, 1H); 6.75(s, 1H); 7.15(d, 1H);          7.7(d, 1H); 6.9-8.45(m, 5H).                                                  16. The starting pyridinium salt, in this case the tetrafluoroborate,         was obtained by reacting 5-bromomethyl-1-methylisatin with 4-                 methylthiopyridine to give 1-(1-methyl-5-isatinylmethyl)-4-                   methylthiopyridinium bromide, m.p. 227.5-228.5 (crystallised from             EtOH). This salt was dissolved in MeOH/H.sub.2 O, 1:1 v/v (30 ml)             and the solution was stirred while silver tetrafluoroborate (1 mM)            in water (5 ml) was added. The yellow silver bromide was filtered             off through kieselguhr, the filter cake was suspended in water (50            ml) and again filtered, and the filtrates were combined and                   evaporated to give the required tetrafluoroborate salt.                   

EXAMPLE 244-245

7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-ethylaminomethylceph-3-em-4-carboxylicacid (205 mg) was dissolved in a mixture of sodium bicarbonate (336 mg)in water (5 ml), and acetonitrile (5 ml).4-Chloro-1-(4-nitrobenzyl)pyridinium chloride (168 mg) was added,stirred for 10 minutes to achieve solution, then stood at roomtemperature overnight. The solvent was evaporated, and the residue waspurified by running on an RP18 column (in sodium salt form), elutingwith H₂ O/CH₃ CN, 100-70:0-30, to give7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-[N-(1-p-nitrobenzyl-4-pyridinio)-N-ethyl]aminomethylceph-3-em-4-carboxylicacid. Yield 27.5%. N.m.r. in solvent A: 1.1 (t, 3H), 1.45 (2xs, 6H);3.2-3.7 (m, 4H); 4.5-4.7 (q, 2H); 5.15 (d, 1H); 5.55 (s, 2 H); 5.85 (d,1H); 6. 7 (s, 1H); 7.1-7.4 (m, 2H); 7.7 (d, 2H); 8.3 (d, 2H); 8.45 (d,2H).

In a similar manner, using the corresponding N-carboxymethyl cephem,there was obtained7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)-acetamido]-3-[N-carboxymethyl-N-(1-p-nitrobenzyl-4-pyridinio]aminomethylceph-3-em-4-carboxylic acid. Yield 19%.

N.m.r. in solvent A: 1.4 (2xs, 6H); 3.25-3.6 (q, 2H); 4.4 (s, 2H); 4.6(s, 2H); 5.15 (d, 1H); 5.55 (s, 2H); 5.85 (d, 1H); 6.7 (s, 1H); 7.05-7.2(m, 1H); 7.4-7.55 (m, 1H); 7.6-7.7 (d, 2H); 8.2-8.3 (d, 2H); 8.4-8.6 (m,2H).

EXAMPLE 246

The process of Example 244 was repeated, using the appropriateN-substituted cephem starting material, to give the following compound:##STR288##

N.m.r. in solvent A: 1.15 (t, 3H); 1.7-1.9 (m, 2H); 2.2-2.5 (m, 4H);3.0-3.5 (q, 2H); 3.5-3.8 (m, 2H); 4.4-4.8 (q, 2H); 5.05 (d, 1H); 5.5 (s,2H); 5.7 (d, 1H); 6.7 (s, 1H); 7.05-7.25 (m, 1H); 7.6-7.7 (m, 3H);8.2-8.3 (d, 2H); 8.35-8.4 (d, 2H).

EXAMPLE 247

3-Acetoxymethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxycyclobutyloxyimino)acetamido]ceph-3-em-4-carboxylicacid (460 mg) was suspended in water (20 ml) with sufficient NaHCO₃ toobtain a solution. 5-Amino-2-methylisoquinolinium iodide (244 mg) wasadded, and the solution was heated under argon for 3hrs. at 85°,maintaining the pH at 7.5 by small additions of HOAC or aqueous NaHCO3.The solution was cooled, made to pH5 with HOAC, and run onto a column ofHP20SS resin. The column was eluted with H₂ O/CH₃ CN, 100-80:0-20. Thefractions containing the product, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxycyclobutyloxyimino)acetamido]-3-[(2-methyl-5-isoquinolinio)aminomethyl]ceph-3-em-4-carboxylicacid, were combined and lyophilised. N.m.r. in solvent A: 1.85 (m, 2H);2.35 (m, 4H); 3.45 (m, 2H); 4.4 (m, 2H); 4.4 (s, 3H); 5.05 (d, 1H); 5.75(d, 1H); 6.75 (s, 1H); 7.3 (d, 1H); 7.55 (d, 1H); 7.75 (t, 1H); 8.54 (d,1H); 8.65 (d, 1H), 9.7 (s, 1H).

EXAMPLE 248

The process described in Example 221 was repeated, using7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(3-pyridylmethylaminomethyl)ceph-3-em-4-carboxylicacid and 1-allyl-4-chloropyridinium bromide as starting materials, togive3-[N-(1-allyl-4-pyridinio)-N-(3-pyridylmethyl)aminomethyl]-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylicacid. N.m.r. in solvent A: 1.65 (s, 3H), 1.7 (s, 3H); 3.35 (d, 1H); 3.7(d, 1H); 4.7-5.3 (m, 7H), 5.4 (d, 1H); 5.5 (d, 1H); 5.95 (d, 1H); 6.1(m, 1H); 7.0 (s, 1H); 7.1-7.5 (br m, 2H); 7.65 (t, 1H); 8.0 (d, 1H); 8.3(m, 2H); 8.7 (s, 2H).

The cephem starting material was obtained as in Example 62, Footnote 14.

1-Allyl-4-chloropyridinium bromide was obtained by quaternising4-chloropyridine with allyl bromide.

EXAMPLES 249-254

The process described in Example 54 was repeated, to obtain thefollowing compounds:

    __________________________________________________________________________     ##STR289##                                                                   Example No.                                                                          R      R.sup.1       Yield %                                                                            Footnotes                                    __________________________________________________________________________    249    Et                                                                                    ##STR290##    6   1, 2                                         250    Et                                                                                    ##STR291##   22   3                                            251    Et                                                                                    ##STR292##   26   4                                            252    (CH.sub.2).sub.2 CN                                                                   ##STR293##   20   5                                            253    H                                                                                     ##STR294##    9   6, 7                                         254    (CH.sub.2).sub.2 CN                                                                   ##STR295##    9   8                                            __________________________________________________________________________    Footnotes                                                                     1. Initially, 1 eq. of quaternary heterocyclic salt and NaHCO.sub.3           reacted with the                                                              CAZAMCA derivative, and further portions of salt and NaHCO.sub.3 were         sub-                                                                          sequently added up to a total of 5 eq. and 10 eq. respectively.               2. Eluant portion 20-35:80-65:1. N.m.r. in solvent B: 1.85(s, 3H);            1.55(s, 6H); 3.5(m,                                                           2H); 3.7(m, 2H); 4.55(d, 1H); 5.15(d, 1H); 5.2(d, 1H); 5.8(d, 1H);            7.05(s, 1H); 7.45(d,                                                          1H); 7.8(d, 1H); 8.2(d, 1H); 9.0(d, 1H).                                      3. Reaction was carried out in DMF, using 2 eq. of Et.sub.3 N in place of     NaHCO.sub.3.                                                                  Eluant portion 25-30:75-70:1. N.m.r. in solvent B: 1.2(t, 3H); 2.15(s,        6H); 3.4-3.8(m,                                                               4H); 4.5-4.8(m, 2H); 5.1(d, 1H); 5.9(d, 1H); 6.05(m, 1H); 7.1(s, 1H);         7.25(s, 1H);                                                                  7.25(m, 1H); 8.35(d, 1H); 8.4(m, 1H); 8.9(m, 1H).                             4. Reaction as in Footnote 3. Eluant proportion 20-25:80-75:1. N.m.r. in      solvent B:                                                                    1.15(t, 3H); 1.55(s, 6H); 3.4(q, 2H); 3.4-3.8(m, 4H); 4.4-5.2(m, 4H);         5.15(d, 1H);                                                                  5.95(d, 1H); 6.95(d, 1H); 7.05(s, 1H); 8.35(d, 1H).                           5. Reaction as in Footnote 3. Eluant proportion 20:80:1. N.m.r. in            solvent B: 1.55(s,                                                            6H); 2.7-3.0(m, 2H); 3.3-4.2(m, 6H); 4.4-4.8(m, 3H); 5.0-5.3(m, 2H);          5.85(d, 1H);                                                                  7.0(s, 1H); 7.15(s, 1H); 8.45(d, 1H).                                         6. Reaction as in Footnote 1, for 2 hr. at room temperature. Eluant           proportion as in                                                              Footnote 4. N.m.r. in solvent B: 1.55(s, 6H); 3.55(s, 2H); 4.55(s, 2H);       4.7(s, 3H);                                                                   5.2(d, 1H); 5.85(d, 1H); 7.05(s, 1H); 7.15(d, 1H); 7.35(d, 1H); 8.05(t,       1H); 8.85(d,                                                                  1H); 9.35(d, 1H).                                                             7. The starting material quarternary heterocyclic salt was obtained from      5-amino-                                                                      cinnoline and methyl iodide. N.m.r. in solvent B: 4.65(s, 3H); 7.2(d,         1H); 7.25(d,                                                                  1H); 7.95(t, 1H); 8.9(d, 1H); 9.25(d, 1H).                                    8. Eluant was MeOH/aqueous ammonium carbonate buffer, 1.3:8.7 v/v. N.m.r.     in                                                                            solvent B; 1.55(s, 6H); 2.7-2.9(m, 2H); 3.3-3.7(m, 2H); 3.8-4.1(m, 2H);       4.6-5.0(m,                                                                    4H); 5.2(d, 1H); 5.2-5.4(m, 2H); 5.9(d, 1H); 7.0(s, 1H); 7.3(d, 1H);          8.3(d, 1H).                                                               

EXAMPLE 255

The process described in Example 61, Footnote 13 was repeated, using7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxycyclobutyloxyimino)acetamido]-3-ethyl-aminoethylceph-3-em-4-carboxylicacid as the cephem starting material, to give3-[N-(1-[2-aminoethyl]-4-pyridinio)-N-ethylaminomethyl]-7-[2-((Z)-1-carboxycyclobutyloxyimino)acetamidolceph-3-em-4-carboxylicacid. The product was purified by MPLC on a HP20SS column eluting withH₂ O/CH₃ CN, 100-93:0-7. N.m.r. in solvent A: 1.1 (t, 3H); 1.85 (m, 2H);2.35 (m, 4H); 3.05 (d, 1H); 3.3 (m, 2H); 3.45 (d, 1H); 3.55-3.8 (m, 2H);4.35-4.5 (m, 3H); 4.8 (d, 1H); 5.05 (d, 1H); 5.7 (d, 1H); 6.75 (s, 1H);7.1 (m, 1H); 7.65 (m, 1H); 8.2 (d, 2H).

EXAMPLE 256

The general process described in Example 6 was repeated, using theappropriate heterocyclic starting material and cephem derivative, togive the following compound in 31% yield: ##STR296##

HPLC eluant MeOH/water/HOAc, 30-35:69-64:1 v/v/v.

N.m.r. in solvent B: 1.3 (t, 3H); 1.7 (m, 4H); 2.15 (m, 4H); 2.95 (q,2H); 3.55 (m, 2H); 4.2 (d, 1H); 4.6 (d, 1H); 5.1 (d, 1H); 5.85 (d, 1H);7.05 (s, 1H); 7.45 (d, 1H); 8.1 (s, 1H); 8.55 (d, 1H).

The starting material was 6-chloro-3-ethylthiazolo[3,2-b]pyridaziniumperchlorate which was prepared by the general procedure described in J.Org. Chem., 34, 996, (1964).

EXAMPLE 257

The process described in Example 247 was repeated, using the appropriate3-acetoxymethyl cephem and 5-amino-2-methylisoquinolinium iodide asstarting materials. The reaction was carried out in water at pH 7.5(adjusted by addition of HOAC or NaHCO₃ as necessary), for 2.5 hrs. at80°. HPLC eluant was MeOH/H₂ O/HOAc, 30-35:69-64:1 v/v/v. N.m.r. insolvent B: 1.7 (m, 4H); 2.15 (m, 4H); 3.6 (m, 2H); 4.4 (m, 5H); 5.15 (d,1H); 5.85 (d, 1H); 7.05 (s, 1H); 7.15 (d, 1H); 7.5 (d, 1H); 7.6 (dd,1H); 7.75 (dd, 1H); 8.5 (d, 1H); 8.65 (d, 1H); 9.75 (s, 1H).

The cephalosporin starting material may be obtained as follows:

To a stirred mixture of DMF (0.85 ml) in anhydrous CH₂ Cl₂ (40 ml) at-10° C. was added dropwise a solution of oxalyl chloride (0.87 ml) inanhydrous CH₂ Cl₂ (10 ml). Stirring was continued at -10° C. for 30minutes. To this stirred suspension was added in one portion2-[(Z)-(tert-butoxycarbonyl)cyclopentyloxyimino]-2-(2-tritylaminothiazol-4-yl)acetic acid (5.97 g) followed byN-methylmorpholine (1.32 ml). Stirring was continued for 30 minutes at-10° C.

In another flask a suspension of 7-aminocephalosporanic acid (2.72 g) inanhydrous CH₂ Cl₂ (25 ml) was stirred for 1 hour with N,O-bis(trimethylsilyl) acetamide (4 ml) to give a clear solution. This wastransferred by syringe to the above acid chloride solution which wasstirred at -10° C. during the addition. The reaction mixture was thenallowed to warm to room temperature and stirred for a further 1.5 hours.The reaction mixture was poured into water and extracted with CH₂ Cl₂.The combined CH₂ Cl₂ extracts were washed with water, dried (MgSO₄) andthe solvent was evaporated under reduced pressure to yield a foam. Thecrude product was dissolved in EtOAc and applied to a column ofKieselgel 60. Elution with EtOAc gave, after precipitation from CH₂ Cl₂with n-hexane,3-acetoxymethyl-7-[2-(2-tritylaminothiazol-4-yl)-2-((Z)-1-tert-butoxycarbonyl)cyclopentyloxyimino)acetamido]ceph-3-em-4-carboxylicacid (6.6g) as a white solid. This compound, (2.61g) was then stirredfor 1 hour at 0° C. with a mixture of TFA (12 ml) and water (1.2 ml).The reaction mixture was evaporated to dryness, the residue taken up inwater and extracted with EtOAc. The solvent was evaporated under reducedpressure to give a solid which was dissolved in a minimum MEOH andprecipitated with ether to give3-acetoxymethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-cyclopentyloxyimino)acetamido]ceph-3-em-4-carboxylicacid (1.1 g) as a white solid having the following n.m.r. in solvent B:1.7 (m, 3H); 1.95 (s, 3H); 2.15 (m, 4H); 3.4 (d, 1H); 3.65 (d, 1H); 4.7(d, 1H); 4.95 (d, 1H); 5.15 (d, 1H); 5.85 (d, 1H); 7.05 (d, 1H).

EXAMPLE 258

Method A of Example 108 was repeated, using the appropriate startingmaterials, and water as solvent to give the compound: ##STR297## in17.5% yield. N.m.r. in solvent B: 2.4-2.7 (m, 4H); 3.4-3.85 (ABq, 2H);4.3-4.7 (Abq, 2H); 5.25 (d, 1H); 5.55 (s, 2H); 5.9 (d, 1H); 6.95 (s,1H); 7.15 (d, 1H); 7.35-7.5 (m, 1H); 7.6 (d, 2H); 8.05 (d, 2H); 8.3 (d,1H); after MPLC on HP20SS (as the sodium salt), and precipitation fromaqueous solution with acetic acid.

The starting quaternary pyridinium salt was the tetrafluoroboratedescribed in Example 243, Footnote 16.

EXAMPLE 259

The process described in Example 221 was repeated, using the appropriate3-ethylaminomethyl cephem and 1-methyl-4-methylthioquinazolinium iodide,to give ##STR298##

n.m.r. in solvent A: 1.4 (br s, 9H); 3.1-3.5 (dd, 2H); 3.98 (br s, 5H);5.04 (d, 1H); 5.1-5.5 (m, 2H); 5.68 (d, 1H); 6.71 (s, 1H); 7.8 (t, 1H);7.99 (d, 1H); 8.12 (t, 1H); 8.28 (d, 1H); 8.85 (s, 1H).

EXAMPLE 260

The process described in Example 236 was repeated, using the appropriate3-aminomethyl cephem and 1-furfuryl-4-methylsulphinylpyridiniumchloride, to give in 20% yield, ##STR299##

n.m.r. in solvent A: 1.42 (2xs 6H); 3.35 (q, 2H); 4.3 (q, 2H); 5.01 (d,1H); 5.37 (s, 2H); 5.67 (d, 1H); 6.45 (q, 1H); 6.62 (d, 1H); 6.73 (s,1H); 6.93 (m, 1H); 7.4 (m, 1H); 7.64 (m, 1H); 8.12 (d, 1H); 8.28 (d,1H).

The starting pyridinium salt was obtained by the general processdescribed in Example 237, Footnote 4. The1-furfuryl-4-methylthiopyridinium chloride had n.m.r. in d₆ -DMSO: 2.72(s, 3H); 5.92 (s, 2H); 6.52 (q, 1H); 6.84 (d, 1H); 7.75 (m, 1H); 8.0 (d,2H); 8.96 (d, 2H). This compound was oxidised to the requiredsulphoxide, as described in Example 237, Footnote 4, and used withoutfurther purification.

EXAMPLE 261

The process described in Examples 1 to 4 was repeated, using theappropriate 3-ethylaminomethyl cephem and 3-chloro-1-methylpyridaziniumiodide. The reaction was carried out for 18 hrs. at room temperaturebefore quenching with HOAc, and isolating the product by chromatographyon Diaion CHP20P resin, to give, in 51% yield, the more polar isomer of##STR300##

n.m.r. spectrum in solvent A: 0.93 (t, 3H); 1.1 (t, 3H); 1.78 (quintet,2H); 3.2 (d, 1H); 3.43 (d, 1H); 3.64 (m, 2H); 4.29 (s, 3H); 4.43 (t,1H); 4.55 (d, 1H); 4.69 (d, 1H); 5.04 (d, 1H); 5.73 (d, 1H); 6.76 (s,1H); 8.05 (m, 2H); 8.93 (t, 1H). Retention time 5.3 minutes on areversed phase Partisil PXS 10/25 ODS-2 column, using MeOH/water/TFA40:60:0.2 v/v/v as eluant.

The cephalosporin starting material may be prepared as follows: To astirred solution of3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxypropoxyimino)acetamido]ceph-3-em-4-carboxylicacid (more polar isomer, 2.6g) in 2.5% (w/v) pH 5.5 sodium acetatebuffer (50 ml) was added sodium cyanoborohydride (0.34 g), followed byacetaldehyde (0.3 ml) in water (5 ml) over 40 minutes. The reactionmixture was then concentrated, diluted to 50 ml with water, and the pHadjusted to 3.5 with HOAc. Careful chromatography on Diaion HP20SS,eluting with H₂ O/CH₃ CN, (92.5:7.5) gave7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxypropoxyimino)acetamido]-3-ethylaminomethylceph-3-em-4-carboxylicacid, having the following n.m.r. spectrum in solvent A: 0.96 (t, 3H);1.18 (t, 3H); 1.81 (quintet, 2H); 2.94 (q, 2H); 3.38 (d, 1H); 3.42 (d,1H); 3.61 (d, 1H); 3.78 (d, 1H), 4.46 (t, 1H); 5.03 (d, 1H); 5.76 (d,1H); 6.88 (s, 1H). Retention time 4.2 minutes on a reversed phasePartisil PXS 10/25 ODS-2 column, using MeOH/H₂ O/HOAc,,30:70:1, v/v/v,as eluant.

EXAMPLE 262

The general process described in Example 244 was repeated, using1-(4-carbamoylbenzyl)-4-chloropyridinium bromide as the startingmaterial, to give ##STR301##

n.m.r. in solvent A: 1.05-1.2 (t, 3H); 1.4 (2xs, 6H); 3.2-3.7 (m, 4H);4.45-4.7 (q, 2H); 5.15 (d, 1H); 5.45 (s, 2H); 5.8 (d, 1H); 6.7 (s, 1H);7.0-7.4 (m, 2H); 7.4-7.5 (d, 2H); 7.85-7.95 (d, 2H); 8.35-8.45 (d, 2H).

The starting pyridinium salt was obtained by quaternising4-chloropyridine with 4-bromomethylbenzamide in DMF at room temperaturefor 4 hours.

EXAMPLES 263-269

The general procedure described in Examples 1-4 was repeated, exceptthat the solvent was DMF and the base was Et₃ N. The appropriate3-ethylaminomethylcephalosporin was used, and products were purified bychromatography on Diaion CHP20P resin. Retention times are quoted for areversed phase Partisil PXS 10/25 ODS-2 column.

The following compounds were made:

    __________________________________________________________________________     ##STR302##                                                                                                     Yield                                       Example                                                                            R.sub.1  R.sub.2             (%) Footnotes                               __________________________________________________________________________    263                                                                                 ##STR303##                                                                             ##STR304##         19  1, 2, 3                                 264                                                                                 ##STR305##                                                                             ##STR306##          5  1, 4, 5                                 265                                                                                 ##STR307##                                                                             ##STR308##         12  6, 7, 8                                 266                                                                                 ##STR309##                                                                             ##STR310##         60  7, 9, 10                                267                                                                                 ##STR311##                                                                             ##STR312##         50  7, 11, 12                               268                                                                                 ##STR313##                                                                             ##STR314##         50  13, 14, 15                              269                                                                                 ##STR315##                                                                             ##STR316##         56  16, 17, 18                              __________________________________________________________________________    1. Starting material was 6-amino-1-methylpyridazinium tetrafluoroborate.      2. Reaction mixture heated 24 hours at 45° C. before quenching         with acetic acid.                                                             3. N.m.r. in solvent A: 0.93(t, 3H), 1.04(t, 3H), 1.8(m, 2H), 3.27(d,         1H), 3.44(d, 1H), 3.48(m,                                                     2H), 3.75(s, 3H), 4.32(d, 1H), 4.47(t, 1H), 4.57(d, 1H), 5.07(d, 1H),         5.88(d, 1H), 6.88(s, 1H),                                                     7.36(d, 1H), 7.75(d, 1H). Retention time 4.6 minutes, eluting with            MeOH/H.sub.2 O/HOAc, 40:60:1,                                                 v/v/v.                                                                        4. Reaction mixture heated at 65° C. for 3 hours before quenching      with acetic acid. After a                                                     preliminary purification on Diaion CHP20P, the product was re-purified by     preparative HPLC                                                              on a reversed phase Partisil ODS2 column, eluting in MeOH/H.sub.2 O/HOAc,     75:25:1 v/v/v.                                                                5. N.m.r. in solvent A: 1.05(t, 3H), 1.39(d, 3H), 3.24(d, 1H), 3.43(d,        1H), 3.48(m, 2H), 3.74(s,                                                     3H), 4.31(d, 1H), 4.53(d, 1H), 4.6(q, 1H), 5.07(d, 1H), 5.75(d, 1H),          6.87(s, 1H), 7.33(d, 1H),                                                     7.88(d, 1H). Retention time 4.5 minutes, eluting with MeOH/water/HOAc,        65:35:1, v/v/v.                                                               6. Starting material 6-fluoro-thiazolo[3,2-b]pyridazinium perchlorate.        7. Reaction carried out at ambient temperature for 18 hours before            quenching with HOAc.                                                          8. N.m.r. in solvent A: 0.92(t, 3H), 1.15(t, 3H), 1.79(m, 2H), 3.32(d,        1H), 3.51(d, 1H), 3.68(m,                                                     2H), 4.45(t, 1H), 4.58(d, 1H), 4.79(d, 1H), 5.05(d, 1H), 5.77(d, 1H),         6.76(s, 1H), 7.89(d, 1H),                                                     8.46(d, 1H), 8.76(d, 1H), 8.78(d, 1H). Retention time 4.7 minutes,            eluting with MeOH/H.sub.2 O/                                                  HOAc, 40:60:1, v/v/v.                                                         9. Starting material was 1-methyl-4-methylthiothieno[2,3-d]pyrimidinium       tetrafluoroborate.                                                            10. N.m.r. in solvent A: 0.9(t, 3H), 1.3(m, 3H), 1.77(m, 2H), 3.24(d,         1H), 3.46(d, 1H), 3.98(m,                                                     2H), 4.0(s, 3H), 4.44(t, 1H), 4.84(d, 1H), 5.06(d, 1H), 5.25(d, 1H),          5.77(d, 1H), 6.76(s, 1H),                                                     7.76(d, 1H), 7.87(d, 1H), 8.77(s, 1H). Retention time 4.1 minutes,            eluting with MeOH/H.sub.2 O/                                                  TFA, 45:65:0.1, v/v/v.                                                        11. Starting material was 6,7-dihydro-2-methylthio-thiazolo [3,2-a]           pyrimidinium tetrafluoro-                                                     borate.                                                                       12. N.m.r. in solvent A: 1.11(t, 3H), 1.39(d, 3H), 3.16(d, 1H), 3.43(d,       1H), 3.66(m, 4H), 4.6(m,                                                      4H), 4.96(d, 1H), 5.06(d, 1H), 5.78(d, 1H), 6.77(s, 1H), 6.83(d, 1H),         8.23(d, 1H). Retention time                                                   5.0 minutes, eluting with MeOH/H.sub.2 O/TFA, 40:60:0.2, v/v/v.               13. Prepared by the standard aqueous/DMF conditions of Examples 1-4,          except that the                                                               reaction was carried out for 65 hours at ambient temperature before           quenching with HOAc.                                                          14. Starting material was 1-allyl-4-chloropyridinium tosylate.                15. N.m.r. in solvent A: 1.12(t, 3H), 1.39(d, 3H), 3.15(d, 1H), 3.45(d,       1H), 3.63(m, 2H), 4.5(d,                                                      1H), 4.58(q, 1H), 4.71(d, 1H), 4.78(d, 2H), 5.06(d, 1H), 5.25(d, 1H),         5.33(d, 1H), 5.77(d, 1H),                                                     6.03(m, 1H), 6.75(s, 1H), 7.1(br, 1H), 7.4(br, 1H), 8.19(d, 2H).              Retention time 3.9 minutes,                                                   eluting with MeOH/H.sub.2 O/TFA, 40:60:0.1, v/v/v.                            16. Prepared using the procedure of Footnote 13 above, except that the        crude product was                                                             chromatographed with out acidification on CHP20P, to give the product as      a mono-sodium                                                                 salt, after precipitation from water by acetone.                              17. Starting material was 4-chloro-1-(4-nitrobenzyl)-pyridinium               tosylate.                                                                     18. N.m.r. in solvent A: 1.11(t, 3H), 1.37(d, 3H), 3.1(d, 1H), 3.51(d,        1H), 3.76(m, 2H), 4.48(d,                                                     1H), 4.57(q, 1H), 4.77(d, 1H), 5.0(d, 1H), 5.52(s, 2H), 5.7(d, 1H),           6.75(s, 1H), 7.1(br, 1H),                                                     7.55(br, 1H), 7.63(d, 2H), 8.25(d, 2H), 8.36(d, 2H). Retention time 8.5       minutes in MeOH/H.sub.2 O/                                                    TFA, 40:60:0.2, v/v/v.                                                         ##STR317##

What we claim is:
 1. A compound of the formula LIV:in which X is sulphuror sulphinyl (R or S configuration); R3 is hydrogen or methoxy; R4 ishydrogen, (1-4C)alkyl, halo(1-4C)alkyl, hydroxy(1-4C)alkyl,(1-4C)alkoxy(1-4C)alkyl, carboxy (1-4C)alkyl, amino(1-4C)alkyl,cyano(1-4)alkyl, (1-4C)alkanoylamino(1-4C)alkyl, allyl, furfuryl, benzylor pyridyl(1-4C)alkyl; R5 is an aromatic heterocyclic ring system whichis linked via carbon and is one of the formula IV to L, excluding XLII,##STR318## each of these ring systems being optionally substituted wherepossible, on a carbon atom or atoms, by one, two or three substituentsselected from halogen, (1-6C)alkyl, carboxy, (2-6C)alkoxycarbonyl,(2-6C)alkoxycarbonyl(1-4C)alkyl, (1-6C)alkoxy, (1-6C)alkylthio, cyano,(2-4C)cyanoalkyl, amino, (1-6C)alkylamino, (2-8C)dialkylamino,benzylamino (optionally substituted in the benzene ring thereof bynitro), thenylamino, allylamino, (1-6C)aminoalkylamino,(1-6C)alkoxy(1-6C)alkylamino, (1-6C)hydroxyalkylamino, hydroxy,mercapto, carbamoyl, (2-6)alkylcarbamoyl, (3-10C)dialkylcarbamoyl,phenylthio and heteroarylthio wherein heteroaryl is a 5- or 6-memberedring containing 1, 2 or 3 hetero atoms selected from oxygen, nitrogenand sulphur and in whichY is oxygen, sulphur or NR27; Z is hydrogen orCH; one of A, B, D and E is +NR27 and the remainder are nitrogen;andring systems of Formula IV, XVI or XVII, ##STR319## which are optionallyfused, or a carbon-carbon bond, with 5- or 7-membered saturatedcarbocyclic ring; R27 is nitrogen-linked and is (1-6C)alkyl,(1-6C)alkyl(2-6C)alkenyl, (2-6C)alkenyl, (2-8C)alkoxyalkyl,carboxy(1-6C)alkyl, [(1-6C)alkoxy]carbonyl(1-6C)alkyl,carbamoyl(1-6C)alkyl, carboxymainocarbonyl(1-6C)alkyl,[(1-6C)alkoxy]carbonylamino-carbonyl(1-6C)alkyl, [(2-8)alkanoyl]methyl,benzoylmethyl, (1-6C)hydroxyalkyl, (1-6C)alkylamino or phenyl(1-6C)alkylor phenyl, each optionally substituted by 1 or 2 groups selected fromhalogen, hydroxy, amino, carboxy, nitro, carbamoyl, cyano,trifluoromethyl, and aminomethyl;R26 is hydrogen, (1-6C)alkyl, phenyl orbenzyl;and the salts formed with acids and bases which affordpharmaceutically acceptable anions and cations, respectively.
 2. Thecephalosporin derivative according to claim 1, wherein R⁵ of the formulaXXII to XXIX.
 3. The cephalosporin derivative according to claim 1,wherein R⁵ is of the formula XXX to XXXVII.
 4. The cephalosporinderivative according to claim 1, wherein R⁵ of the formula XL to XLI. 5.The cephalosporin derivative according to claim 1, wherein R⁵ is of theformula XLIII, XLVI to L.
 6. The cephalosporin derivative according toclaim 1, wherein R⁵ is of the formula XLIV to XLV.
 7. The cephalosporinderivative according to claim 1, wherein R⁵ is of the formula XXXVIII toXXXIX.
 8. The cephalosporin derivative according to claim 1, wherein R⁵is of the formula IV.
 9. The cephalosporin derivative according to claim1, wherein R⁵ is of the formula V.
 10. The cephalosporin derivativeaccording to claim 1, wherein R⁵ is of the formula VI to XI.
 11. Thecephalosporin derivative according to claim 1, wherein R⁵ is of theformula XII to XIII.
 12. The cephalosporin derivative according to claim1, wherein R⁵ is of the formula XIV to XV or XVIII.
 13. A cephalosporinderivative as claimed in claim 1 whereinthe ring substituents areselected from chlorine, fluorine, methyl, ethyl, n-propyl, isopropyl,carboxy, methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxy, ethoxy,methylthio, amino, isopropylamino, dimethylamino, p-nitrobenzylamino,allylamino, 2-aminoethylamino, 2-methoxyethylamino, 2-hdyroxyethylaminoand hydroxy; R27 is (1-6C)alkyl, allyl or phenyl optionally substitutedby nitro or trifluoromethyl; and R4 is hydrogen, (1-4C)alkyl,halo(1-4C)alkyl, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl,carboxy(1-4C)alkyl, amino(1-4C)alkyl, cyano(1-4C)alkyl,(1-4C)alkanoylamino(1-4C)alkyl, allyl, furfuryl, benzl orpyridyl(1-4C)alkyl.
 14. A cephalosporin derivative as claimed in claim13 whereinthe ring substituents are selected from chlorine, fluorine,methyl, ethyl, n-propyl, isopropyl, carboxy, methoxycarbonylmethyl,ethoxycarbonylmethyl, methoxy, ethoxy, methylthio, amino,isopropylamino, dimethylamino, p-nitrobenzylamino, allylamino,2-aminoethylamino, 2-methoxyethylamino, 2-hdyroxyethylamino and hydroxy;and R4 is hydrogen, methyl, ethyl, 2-fluoroethyl, 2-chloroethyl,2-hydroxyethyl, 2-methoxyethyl, carboxymethyl, 2-aminoethyl,2-cyanoethyl, 2-formamidoethyl, allyl, furfuryl, benzyl or4-pyridylmethyl.
 15. A cephalosporin derivative as claimed in claim 1wherein R5 is of the formula XVI wherein the ring is substituted by(1-6C)alkyl and/or amino; of the formula XXVIII wherein Y is sulphur, Zis CH₂ and R27 is (1-6C)alkyl; or of the formula XLIII wherein Y issulphur; of the formula XLVI wherein the optional bond is a double bond;of the formula XLVII wherein R27 is methyl.
 16. A cephalosporinderivative of the formula LIV: ##STR320## in which X has the meaningstated in claim 1: R3 is hydrogen or methoxy;R4 is hydrogen, methyl,ethyl, n-propyl, isopropyl, 2-fluoroethyl, 2-chloroethyl,2-hydroxymethyl, 2-methoxyethyl, carboxymethyl, (R) and(S)-1-carboxyethyl, 2-aminoethyl, 2-cyanoethyl, 2-formamidoethyl, allyl,furfuryl, benzyl or 4-pyridylmethyl; R5 has the meaning stated in claim13, wherein the optional substituent on one of the ring systems of theformula IV to L, excluding XLII, is one, two or three substituentsselected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl,isopropyl, carboxy, methoxycarbonyl, ethoxycarbonyl,methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxy, ethoxy, methyl,ethylthio, cyano, cyanomethyl, 2-cyanoethyl, amino, methylamino,ethylamino, isopropylamino, dimethylamino, benzylamino, (optionallysubstituted in the benzene ring by nitro), allylamino,2-aminoethyl-amino, 2-methoxyethylamino, 2-hydroxyethylamino, hydroxy,mercapto, carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl,phenylthio, and heteroarylthio in which the heteroaryl ring is a furan,thiophene, imidazole, thiazole, pyrazole, thiadiazole, pyridine,pyrimidine, pyrazine or pyridazine; R27 is methyl, ethyl, n-propyl,isopropyl, allyl, methoxymethyl, 2-methoxyethyl, carboxymethyl,2-carboxyethyl, methoxycarbonylmethyl, 2-methoxycarbonylethyl,carbamoylmethyl, carbamoylethyl, carboxyaminocarbonylmethyl,2-(carboxyaminocarbonyl)ethyl, methoxycarbonylaminocarbonylmethyl,2-(methoxycarbonylaminocarbonyl)ethyl, acetylmethyl, propionylmethyl,benzoylmethyl, hydroxymethyl, 2-hydroxyethyl, methylamino, ethylamino,benzyl or 2-phenethyl, or phenyl optionally substituted by 1 or 2 groupsselected from fluorine, chlorine, bromine hydroxy, amino, carboxy,nitro, carbamoyl, cyano, trifluoromethyl and aminomethyl; R26 ishydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl or benzyl; and thehydrochloride, hydrobromide, phosphate, sulphate, citrate or maleatethereof, and the potassium, magnesium, triethylamine, morpholine,N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine orN,N'-dibenzylethylenediamine salts thereof, and other amine salts whichhave been used with cephalosporins.
 17. A cephalosporin derivative asclaimed in claim 1 and 16 wherein R3 is hydrogen, X is sulphur, R4 ishydrogen, methyl or ethyl, and R5 is of the formula XVI, XXVIII, XLIII,XLVI, or XLVII, ##STR321## these ring systems being optionallysubstituted, where possible, on a carbon atom or atoms, by one or twosubstituents selected from halogen, (1-6C)alkyl, carboxy,(2-6C)alkoxycarbonyl(1-4C)alkyl, (1-6C)alkoxy, (1-6C)alkylthio, amino(1-6C)alkylamino, 2-8C)dialkylamino, benzylamino optionally substitutedin the benzene ring thereof by nitro, allylamino, (1-6C)aminoalkylamino,(1-6C)-alkoxy(1-6C)alkylamino, (1-6C)hydroxyalkylamino and hydroxy.